N-Fmoc-D-1,2,3,4-四氢异喹啉-3-羧酸 | 130309-33-0

• 物质功能分类: 生物化工 - 氨基酸及其衍生物 - FMOC-氨基酸
• 分子结构分类: 有机化合物 - 苯类化合物 - 芴
• 中文名称: N-Fmoc-D-1,2,3,4-四氢异喹啉-3-羧酸
• 中文别名: (R)-(-)-2-(9-芴甲氧羰基)1,2,3,4-四氢-3-异喹啉羧酸；N-FMOC-1,2,3,4-四羟基异喹啉-3-甲酸；(R)-N-芴甲氧羰基-1,2,3,4-四氢异喹啉-3-羧酸；芴甲氧羰基-D-1,2,3,4-四氢异喹啉-3-羧酸；FMOC-D-四氢异喹啉-3-羧酸
• 英文名称: N-Fmoc-D-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid
• 英文别名: Fmoc-D-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid；Fmoc-D-1,2,3,4-tetraisoquinoline-3-carboxylic acid；Fmoc-D-Tic-OH；Fmoc-D-Tic；fmoc-D-tetrahydroisoquinoline-1-carboxylic acid；Fmoc-(D)Tic-OH；(3R)-2-(9H-fluoren-9-ylmethoxycarbonyl)-3,4-dihydro-1H-isoquinoline-3-carboxylic acid
• CAS: 130309-33-0
• 化学式: C₂₅H₂₁NO₄
• 分子量: 399.446
• InChiKey: LIRBCUNCXDZOOU-HSZRJFAPSA-N

物化性质

• 熔点：
  160-164 °C
• 沸点：
  522.37°C (rough estimate)
• 密度：
  1.2390 (rough estimate)
• 溶解度：
  溶于氯仿、二氯甲烷、乙酸乙酯、DMSO、丙酮等。

计算性质

• 辛醇/水分配系数(LogP)：
  4.4
• 重原子数：
  30
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.2
• 拓扑面积：
  66.8
• 氢给体数：
  1
• 氢受体数：
  4

安全信息

• 危险等级：
  IRRITANT
• 危险品标志：
  Xi
• 安全说明：
  S24/25
• WGK Germany：
  3
• 海关编码：
  29334900
• 危险类别：
  IRRITANT
• 危险性防范说明：
  P261,P305+P351+P338
• 危险性描述：
  H302,H315,H319,H335

反应信息

• 作为反应物：
  描述：

  N-Fmoc-D-1,2,3,4-四氢异喹啉-3-羧酸 在 氯化亚砜 作用下， 以 二氯甲烷 为溶剂， 反应 2.0h， 生成 Fmoc-D-Tic acid chloride
  参考文献：
  名称：

  Bradykinin Receptor Antagonists Containing N-Substituted Amino Acids:  In Vitro and in Vivo B₂ and B₁ Receptor Antagonist Activity

  摘要：

  We report a systematic probing of the structural requirements of the bradykinin (BK) type 2 (B-2) receptor for antagonist activity by incorporating N-Alkyl-amino acid residues at positions 7 and 8 of a potent antagonist sequence. Compound 1 (D-Arg(0)-Arg(1)-Pro(2)-Hyp(3)-Gly(4)-Thi(5)-Ser(6)- D-Tic(7)-N-Chg(8)-Arg(9), CP-0597)(1,2) is a potent (pA(2) = 9.3, rat uterus; pK(i) = 9.62, binding, human receptor clone) Bz receptor antagonist devoid of in vitro B-1 antagonist activity (rabbit aorta). Compound 1 exhibits high potency (ED(50) = 29.2 pmol/kg/min, iv, rabbit) and duration of action when tested in models for in vivo B-2 antagonist activity. Although devoid of activity in a classic B-1 isolated tissue assay, B-1 antagonist activity for 1 was demonstrated in vivo, in a LPS-treated, inducible BK1 receptor rabbit blood pressure model (ED(50) = 1.7 nmol/kg/min). D-Arg(0) of 1 can be formally replaced by an achiral arginine surrogate, without significant loss in antagonist potency on rat uterus (compound 11, B-2 pA(2) = 9.1). Antagonist 13 (Hyp(2), NChg(8)), pK(i) = 10.2, and agonist 4 (N-methylcyclohexyl-Gly(8)), pK(i) = 10.1, also exhibited substantial binding to guinea pig ileum membrane receptors as well as a human Bz receptor clone. Very minor structural changes in the N-alkyl amino acid residues in positions 7 and 8 can modify the activity of this class of compounds from being extremely potent antagonists to tight binding partial or full agonists. These studies have resulted in a series of compounds containing inexpensive amino acid residues but which produce broad spectrum BK receptor blocking potency and exceptional in vivo duration of action.

  DOI：

  10.1021/jm950716i

文献信息

• [EN] COMPOUNDS CONTAINING MATRIX METALLOPROTEINASE SUBSTRATES AND METHODS OF THEIR USE<br/>[FR] COMPOSES CONTENANT DES SUBSTRATS DE METALLOPROTEINASE MATRICIELLE ET PROCEDES D'UTILISATION ASSOCIES
  申请人：BRISTOL MYERS SQUIBB CO

  公开号：WO2005023314A1

  公开（公告）日：2005-03-17

  Compounds for use in a diagnostic agent for detecting, imaging, and/or monitoring a pathological disorder associated with matrix metalloproteinase activity at a site of interest in a patient are disclosed. Compositions and kits containing the compounds are also disclosed. In addition, methods of detecting, imaging, and/or monitoring the presence of matrix metalloproteinase or a pathological disorder associated with matrix metalloproteinase activity in a patient are disclosed.

  揭示了用于诊断剂的化合物，用于检测、成像和/或监测患者感兴趣部位处与基质金属蛋白酶活性相关的病理紊乱。还揭示了含有这些化合物的组合物和试剂盒。此外，还揭示了检测、成像和/或监测患者体内基质金属蛋白酶或与基质金属蛋白酶活性相关的病理紊乱存在的方法。
• Selective Substrates and Activity-Based Probes for Imaging of the Human Constitutive 20S Proteasome in Cells and Blood Samples
  作者：Wioletta Rut、Marcin Poręba、Paulina Kasperkiewicz、Scott J. Snipas、Marcin Drąg

  DOI：10.1021/acs.jmedchem.8b00026

  日期：2018.6.28

  the HyCoSuL approach, we designed and synthesized novel and selective fluorogenic substrates for each of these three constitutive 20S proteasome activities and applied them to assess inhibition of proteasome subunits by MG-132 and a clinically used inhibitor bortezomib. Our results confirm the utility of designed substrates in biochemical assays. Furthermore, selective peptide sequences obtained in this

  蛋白酶体是维持蛋白质稳态的关键酶复合物。蛋白酶体功能紊乱导致包括癌症，自身免疫和神经退行性疾病在内的病理。因此，蛋白酶体构成药物开发的极好的分子靶标。在这里，我们使用HyCoSuL方法为这三个20S组成型蛋白酶体活性中的每一个设计和合成了新颖的选择性荧光底物，并将它们应用于评估MG-132和临床使用的硼替佐米对蛋白酶体亚基的抑制作用。我们的结果证实了设计的底物在生化分析中的实用性。此外，以此方式获得的选择性肽序列用于构建荧光团标记的基于活性的探针，然后用于同时检测HEK-293F细胞和红细胞裂解液中的每个20S组成型蛋白酶体亚基。总体而言，我们描述了一种简单而快速的方法，可用于测量全血样本中20S组成型蛋白酶体的活性，该方法可以早期诊断与异常上调的蛋白酶体活性有关的病理状态。
• Synthesis and biological activity of oxytocin analogues containing conformationally-restricted residues in position 7
  作者：Maria Fragiadaki、Vassiliki Magafa、Lenka Borovicková、Jiřina Slaninová、Paul Cordopatis

  DOI：10.1016/j.ejmech.2006.12.016

  日期：2007.6

  having one more modification in position 3, i.e. Gly(Bu(t)), and three analogues having glycine in position 9 substituted by d-Tic or Aib, were prepared. The analogues were tested for rat uterotonic activity in vitro, in the rat pressor assay and for binding affinity to human OT receptor. The analogue having the highest antioxytocic activity was [Mpa(1), D-Tyr(Et)(2), D-Tic(7), Aib(9)]OT having pA(2)=8

  我们报告了二十种催产素（OT）类似物的固相合成和一些药理特性。7位的基本修饰（引入α-氨基异丁酸[Aib]，L-或D-1,2,3,4-四氢异喹啉-3-羧酸[L / D-Tic]，L-α-叔丁基甘氨酸[Gly（Bu（t））]和胡椒酸[Pip]）与D-Tyr（Et）（2），L / D-（pEt）Phe（2），D-Tic（2）和Mpa合并（1）总共14个类似物的修饰及其各种组合。另外，制备了在3位具有一个或多个修饰的类似物，即Gly（Bu（t）），和在9位具有甘氨酸的三个类似物被d-Tic或Aib取代。在大鼠中，在大鼠加压试验中测试了类似物的大鼠子宫内膜活性，以及​​与人OT受体的结合亲和力。具有最高抗氧活性的类似物为[Mpa（1），D-Tyr（Et）（2），D-Tic（7），Aib（9）] OT具有pA（2）= 8.31 +/- 0.19; 该类似物也是选择性的。
• [EN] A METHOD FOR PRODUCTION OF HIGH PURITY ICATIBANT<br/>[FR] PROCÉDÉ DE PRODUCTION D'ICATIBANT DE HAUTE PURETÉ
  申请人：FRESENIUS KABI IPSUM S R L

  公开号：WO2019202057A1

  公开（公告）日：2019-10-24

  The present invention provides a process for the manufacture of peptidomimetic drug icatibant with high yield and purity by fragment condensation on the solid phase. In particular, it describes a convergent synthesis by condensation of a protected C-terminal fragment bound to a solid support and a protected N-terminal fragment, followed by cleavage from the support and resulting in a crude peptide of high purity, which is further purified to obtain pure icatibant in high yield. The invention further provides intermediates useful in the manufacturing process.

  本发明提供了一种高产率和高纯度制备肽类拟药物icatibant的方法，该方法通过在固相上进行片段缩合实现。具体而言，它描述了一种通过将保护的C-末端片段与固定在固相支持物上的保护的N-末端片段缩合的汇聚合成方法，随后从支持物上解离，得到高纯度的粗肽，进一步纯化以获得高产率的纯净icatibant。该发明还提供了在制造过程中有用的中间体。
• [EN] SYNTHESIS OF ICATIBANT<br/>[FR] SYNTHÈSE DE L'ICATIBANT
  申请人：BIOCON LTD

  公开号：WO2019064220A1

  公开（公告）日：2019-04-04

  The present invention relates to the efficient solid-phase synthesis of Icatibant represented by Formula (I). The present invention relates to an efficient process for the preparation of Icatibant by sequential coupling employing solid phase approach. It involves sequential coupling of protected amino acids to prepare Icatibant. The present invention also involves the usage of inorganic salts during the coupling, wash with HOBt in DMF solution after Fmoc-deprotection step to ensure complete removal of piperidine and reactions are going for completion, and thus avoid addition/deletion sequences and also improve the process yield.

  本发明涉及以固相合成的高效方法制备由化学式（I）表示的伊卡替班。本发明涉及一种通过顺序偶联采用固相方法制备伊卡替班的高效过程。它涉及保护氨基酸的顺序偶联以制备伊卡替班。本发明还涉及在偶联过程中使用无机盐，在Fmoc去保护步骤后用HOBt在DMF溶液中清洗，以确保完全去除哌啶并使反应进行到完成，从而避免添加/删除序列，并提高工艺产量。