(R)-1-n-boc-4-n-boc-哌嗪-2-羧酸 | 173774-48-6

• 物质功能分类: 医药中间体 - 杂环化合物 - 哌嗪类化合物
• 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
• 中文名称: (R)-1-n-boc-4-n-boc-哌嗪-2-羧酸
• 中文别名: (R)-1-N-BOC-4-N-BOC-哌嗪-2-甲酸；(2R)-1,2,4-哌嗪三羧酸-1,4-二(1,1-二甲基乙基)酯
• 英文名称: (R)-1,4-bis(tert-butoxycarbonyl)piperazine-2-carboxylic acid
• 英文别名: (2R)-1,4-bis[(2-methylpropan-2-yl)oxycarbonyl]piperazine-2-carboxylic acid
• CAS: 173774-48-6
• 化学式: C₁₅H₂₆N₂O₆
• 分子量: 330.381
• InChiKey: IIZGWFQKLVCLLA-SNVBAGLBSA-N

物化性质

• 沸点：
  443.9±40.0 °C(Predicted)
• 密度：
  1.200±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.4
• 重原子数：
  23
• 可旋转键数：
  5
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.8
• 拓扑面积：
  96.4
• 氢给体数：
  1
• 氢受体数：
  6

安全信息

• 海关编码：
  2933599090
• 危险性防范说明：
  P261,P305+P351+P338
• 危险性描述：
  H302,H315,H319,H335
• 储存条件：
  存储条件：2-8℃，请保持干燥。

反应信息

• 作为反应物：
  描述：

  (R)-1-n-boc-4-n-boc-哌嗪-2-羧酸 在 吡啶 、 氯化亚砜 作用下， 以 DMF (N,N-dimethyl-formamide) 、 乙腈 为溶剂， 反应 18.0h， 生成 N-Boc-piperazine-2-amidoanhydride
  参考文献：
  名称：

  NOVEL INHIBITORS OF FARNESYL-PROTEIN TRANSFERASE

  摘要：

  公开号：

  EP1140909B1
• 作为产物：
  描述：

  (R)-1,4-二-Boc-哌嗪-2-羧酸甲酯 在 potassium hydroxide 作用下， 以 乙醇 为溶剂， 反应 18.0h， 以94%的产率得到(R)-1-n-boc-4-n-boc-哌嗪-2-羧酸
  参考文献：
  名称：

  [EN] AZAQUINAZOLINE INHIBITORS OF ATYPICAL PROTEIN KINASE C
  [FR] INHIBITEURS DE TYPE AZAQUINAZOLINE DE PROTÉINE KINASE C ATYPIQUE

  摘要：

  公开号：

  WO2014052699A9

文献信息

• [EN] SULFONYLPIPERAZINE DERIVATIVES THAT INTERACT WITH GLUCOKINASE REGULATORY PROTEIN FOR THE TREATMENT OF DIABETES<br/>[FR] DÉRIVÉS DE SULFONYLPIPÉRAZINE QUI INTERAGISSENT AVEC LA PROTÉINE RÉGULATRICE DE LA GLUCOKINASE POUR LE TRAITEMENT DU DIABÈTE
  申请人：AMGEN INC

  公开号：WO2012027261A1

  公开（公告）日：2012-03-01

  The present invention relates to compounds of Formula I, or pharmaceutically acceptable salts thereof, that interact with glucokinase regulatory protein. In addition, the present invention relates to methods of treating type 2 diabetes, and other diseases and/or conditions where glucokinase regulatory protein is involved using the compounds, or pharmaceutically acceptable salts thereof, and pharmaceutical compositions that contain the compounds, or pharmaceutically acceptable salts thereof.

  本发明涉及与葡萄糖激酶调节蛋白相互作用的化合物I式，或其药用盐，此外，本发明涉及使用这些化合物或其药用盐治疗2型糖尿病和其他涉及葡萄糖激酶调节蛋白的疾病和/或症状的方法，以及含有这些化合物或其药用盐的药物组合物。
• Antidiabetic effects of glucokinase regulatory protein small-molecule disruptors
  作者：David J. Lloyd、David J. St Jean、Robert J. M. Kurzeja、Robert C. Wahl、Klaus Michelsen、Rod Cupples、Michelle Chen、John Wu、Glenn Sivits、Joan Helmering、Renée Komorowski、Kate S. Ashton、Lewis D. Pennington、Christopher Fotsch、Mukta Vazir、Kui Chen、Samer Chmait、Jiandong Zhang、Longbin Liu、Mark H. Norman、Kristin L. Andrews、Michael D. Bartberger、Gwyneth Van、Elizabeth J. Galbreath、Steven L. Vonderfecht、Minghan Wang、Steven R. Jordan、Murielle M. Véniant、Clarence Hale

  DOI：10.1038/nature12724

  日期：2013.12

  Two small-molecule disruptors of the glucokinase–glucokinase-regulatory-protein complex, AMG-1694 and AMG-3969, are identified that decrease blood glucose levels in various models of hyperglycaemic rodents. Glucokinase (GK) is involved in the regulation of glucose homeostasis and is an important target for drug discovery against diabetes, but some current GK activators are associated with an increased risk for hypoglycaemia in the clinic. This paper presents an alternative therapeutic point of intervention, focused on the liver-specific GK regulatory protein (GKRP) that binds and inhibits GK in the nucleus. David Lloyd et al. report on a small molecule, AMG-1694, that specifically disrupts the GK–GKRP complex and reduces blood glucose in hyperglycaemic rodent models. Importantly AMG-1694 has no effect in normoglycaemic animals. Disruption of the GK–GKRP complex offers a liver-specific approach of upregulating GK activity in type II diabetes while reducing the risk of hypoglycaemia. Glucose homeostasis is a vital and complex process, and its disruption can cause hyperglycaemia and type II diabetes mellitus1. Glucokinase (GK), a key enzyme that regulates glucose homeostasis, converts glucose to glucose-6-phosphate2,3 in pancreatic β-cells, liver hepatocytes, specific hypothalamic neurons, and gut enterocytes4. In hepatocytes, GK regulates glucose uptake and glycogen synthesis, suppresses glucose production3,5, and is subject to the endogenous inhibitor GK regulatory protein (GKRP)6,7,8. During fasting, GKRP binds, inactivates and sequesters GK in the nucleus, which removes GK from the gluconeogenic process and prevents a futile cycle of glucose phosphorylation. Compounds that directly hyperactivate GK (GK activators) lower blood glucose levels and are being evaluated clinically as potential therapeutics for the treatment of type II diabetes mellitus1,9,10. However, initial reports indicate that an increased risk of hypoglycaemia is associated with some GK activators11. To mitigate the risk of hypoglycaemia, we sought to increase GK activity by blocking GKRP. Here we describe the identification of two potent small-molecule GK–GKRP disruptors (AMG-1694 and AMG-3969) that normalized blood glucose levels in several rodent models of diabetes. These compounds potently reversed the inhibitory effect of GKRP on GK activity and promoted GK translocation both in vitro (isolated hepatocytes) and in vivo (liver). A co-crystal structure of full-length human GKRP in complex with AMG-1694 revealed a previously unknown binding pocket in GKRP distinct from that of the phosphofructose-binding site. Furthermore, with AMG-1694 and AMG-3969 (but not GK activators), blood glucose lowering was restricted to diabetic and not normoglycaemic animals. These findings exploit a new cellular mechanism for lowering blood glucose levels with reduced potential for hypoglycaemic risk in patients with type II diabetes mellitus.

  两种小分子破坏剂AMG-1694和AMG-3969能够破坏葡糖激酶-葡糖激酶调节蛋白复合体，降低高血糖啮齿动物模型的血糖水平。葡糖激酶（GK）参与调节血糖内平衡，是针对糖尿病发现药物的重要靶点，但是一些现有的GK活化剂会导致临床患者发生低血糖的风险上升。在这篇文章中我们介绍了一个新的治疗干预点，专注于与GK在细胞核中结合并抑制GK、具有肝脏特异性的葡糖激酶调节蛋白（GKRP）。大卫·劳埃德等人报告了一个可特异性破坏GK-GKRP复合体，在啮齿类高血糖模型中降低血糖的小分子AMG-1694。重要的是，AMG-1694对血糖正常的动物没有作用。破坏GK-GKRP复合体提供了只针对肝脏上调II型糖尿病患者的GK活性的方法，同时降低了低血糖的风险。血糖内平衡是一个非常重要的、复杂的过程，其受到破坏会导致高血糖和II型糖尿病。葡糖激酶是调节血糖内平衡的一个关键酶，在胰腺β-细胞、肝脏肝细胞、特定下丘脑神经元和肠道上皮细胞中将葡萄糖转化成6-磷酸葡糖。在肝脏肝细胞中，GK调节葡萄糖摄取和糖原合成，抑制葡萄糖生成，受到内源性抑制剂GK调节蛋白的抑制。空腹期间，GK调节蛋白结合GK、使GK失活并将GK裹入细胞核，GK因此不参与糖异生过程，不会出现葡萄糖磷酸化的无效循环。直接超活化GK（GK活化剂）的化合物可降低血糖水平，作为可能的治疗I型糖尿病的药物正在接受临床评估。但是最初的报告表明，一些GK活化剂在使用时会增加低血糖的风险。为了降低低血糖发生的风险，我们试图通过抑制GK调节蛋白增加GK活性。本文介绍了两种破坏GK-GKRP复合体的小分子AMG-1694和AMG-3969，它们使糖尿病啮齿类动物模型的血糖水平恢复正常。这两种化合物都能逆转GK调节蛋白对GK活性的抑制效应，促进GK定位转移，不论是在体外分离出的肝细胞中还是在体内的肝脏组织中。AMG-1694与全长人类GK调节蛋白形成的复合体的共晶体结构显示，GK调节蛋白存在一个不同于磷酸果糖结合位点的未知结合口袋。此外，使用AMG-1694和AMG-3969（而非GK活化剂）降低血糖仅对糖尿病模型动物有效，而不会影响正常动物的血糖水平。本研究利用一种新的细胞机制降低II型糖尿病患者的血糖水平，发生低血糖的风险较低。
• Small Molecule Disruptors of the Glucokinase–Glucokinase Regulatory Protein Interaction: 1. Discovery of a Novel Tool Compound for in Vivo Proof-of-Concept
  作者：Kate S. Ashton、Kristin L. Andrews、Marion C. Bryan、Jie Chen、Kui Chen、Michelle Chen、Samer Chmait、Michael Croghan、Rod Cupples、Christopher Fotsch、Joan Helmering、Steve R. Jordan、Robert J. M. Kurzeja、Klaus Michelsen、Lewis D. Pennington、Steve F. Poon、Glenn Sivits、Gwyneth Van、Steve L. Vonderfecht、Robert C. Wahl、Jiandong Zhang、David J. Lloyd、Clarence Hale、David J. St. Jean

  DOI：10.1021/jm4016735

  日期：2014.1.23

  Small molecule activators of glucokinase have shown robust efficacy in both preclinical models and humans. However, overactivation of glucokinase (GK) can cause excessive glucose turnover, leading to hypoglycemia. To circumvent this adverse side effect, we chose to modulate GK activity by targeting the endogenous inhibitor of GK, glucokinase regulatory protein (GKRP). Disrupting the GK-GKRP complex

  葡萄糖激酶的小分子激活剂在临床前模型和人类中均显示出强大的功效。但是，葡萄糖激酶（GK）的过度激活会导致过多的葡萄糖周转，从而导致低血糖症。为了避免这种不良副作用，我们选择通过靶向GK的内源性抑制剂葡萄糖激酶调节蛋白（GKRP）来调节GK活性。破坏GK-GKRP复合物会导致未结合的胞质GK数量增加，而不会改变酶的固有动力学。本文中，我们报告了通过先前未知的结合口袋有效破坏GK-GKRP相互作用的化合物的鉴定。使用基于结构的方法，初始命中的效力提高到提供25（AMG-1694）。在ZDF大鼠中给药25显示出强大的药效作用以及葡萄糖的统计学显着降低。另外，在高血糖或正常大鼠中均未观察到低血糖。
• [EN] PIPERAZINES AS ANTI-OBESITY AGENTS<br/>[FR] PIPÉRAZINES COMME AGENTS ANTI-OBÉSITÉ
  申请人：BIOVITRUM AB PUBL

  公开号：WO2009071658A1

  公开（公告）日：2009-06-11

  The present invention relates to new compounds of formula (I), to pharmaceutical compositions comprising these compounds, to processes for their preparation, and to the use of these compounds as leptin receptor modulator mimetics in the preparation of medicaments against conditions associated with weight gain, type 2 diabetes and dyslipidemias.

  本发明涉及公式（I）的新化合物，包括这些化合物的药物组合物，其制备方法，以及将这些化合物用作在制备针对与体重增加、2型糖尿病和血脂异常相关疾病的药物中的瘦素受体调节剂拟拟物。
• Human Adam-10 Inhibitors
  申请人：Naganathan Sriram

  公开号：US20110003812A1

  公开（公告）日：2011-01-06

  Magnesium salts/complexes of compounds useful for inhibiting the ADAM-IO protein and methods of making and purifying them are provided. Further provided are compositions comprising magnesium salts/complexes of the compounds in combination with a pharmaceutically acceptable carrier. The compounds well as such compositions comprising them are useful for the treatment of cancer, arthritis, diseases related to angiogenesis, such as renal diseases, heart diseases, such as heart failure, atherosclerosis, and stroke, inflammation, ulcer, infertility, scleroderma, endometriosis, mesothelioma, and diabetes. In addition, methods of treating forms of cancer, arthritis, and diseases related to angiogenesis in which ADAM-10 plays a critical role are provided.

  提供了用于抑制ADAM-IO蛋白质的镁盐/化合物络合物及其制备和纯化方法。此外，还提供了包含镁盐/化合物络合物的组合物，与药用载体结合。这些化合物以及包含它们的组合物对于治疗癌症、关节炎、与血管生成有关的疾病，如肾脏疾病、心脏疾病，如心力衰竭、动脉粥样硬化和中风、炎症、溃疡、不孕症、硬皮病、子宫内膜异位症、间皮瘤和糖尿病方面具有用处。此外，还提供了治疗癌症、关节炎和与ADAM-10发挥关键作用的血管生成相关疾病的方法。