4-[1-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethylamino]methylpiperidine | 337340-02-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: 4-[1-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethylamino]methylpiperidine
• 英文别名: 4-(Dde-aminomethyl)piperidine；5,5-dimethyl-2-[1-(piperidin-4-ylmethylamino)ethylidene]cyclohexane-1,3-dione
• CAS: 337340-02-0
• 化学式: C₁₆H₂₆N₂O₂
• mdl: MFCD01810977
• 分子量: 278.395
• InChiKey: DQDVSSDPKFHYJL-UHFFFAOYSA-N

物化性质

• 熔点：
  104-107 °C(Solv: methanol (67-56-1); ethyl ether (60-29-7))
• 沸点：
  420.3±45.0 °C(Predicted)
• 密度：
  1.042±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.81
• 重原子数：
  20.0
• 可旋转键数：
  3.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.75
• 拓扑面积：
  58.2
• 氢给体数：
  2.0
• 氢受体数：
  4.0

反应信息

• 作为反应物：
  描述：

  4-[1-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethylamino]methylpiperidine 在 1-羟基苯并三唑 、 N,N-二异丙基乙胺 、 N,N'-二环己基碳二亚胺 、 肼 作用下， 以 甲醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 55.5h， 生成 6-Guanidino-hexanoic acid (1-phenylacetyl-piperidin-4-ylmethyl)-amide
  参考文献：
  名称：

  Design and Synthesis of Novel Biologically Active Thrombin Receptor Non-Peptide Mimetics Based on the Pharmacophoric Cluster Phe/Arg/NH₂ of the Ser₄₂-Phe-Leu-Leu-Arg₄₆ Motif Sequence:  Platelet Aggregation and Relaxant Activities

  摘要：

  The identification of the thrombin receptor has promoted the interest for the development of new therapeutic agents capable of selectively inhibiting unwanted biological effects of thrombin on various cell types. In this study we have designed and synthesized two series of new thrombin receptor antagonists based on the thrombin receptor motif sequence S42FLLR46, one possessing two (Phe/Arg) pharmacophoric groups and the other possessing three (Phe/Arg/NH2). N-(6-Guanidohexanoyl)-N'-(phenylacetyl)piperazine (1), N-(phenylacetyl)-4-(6-guanidohexanoylamidomethyl)piperidine (2), and N-(phenylacetyl)-3-(6-guanidohexanoylamido)pyrrolidine (3) (group A) carry the two pharmacophoric side chains of Phe and Arg residues incorporated on three different templates (piperazine, 4-aminomethylpiperidine, and 3-aminopyrrolidine). Compounds with three pharmacophoric groups (group B) were built similarly to group A using the same templates with the addition of an extra methylamino group leading to (S)-N-(6-guanidohexanoyl)-N'-(2-amino-3-phenylpropionyl)piperazine (4), (S)-N-(2-amino-3-phenylpropionyl)-4-(6-guanidohexanoylamidomethyl)piperidine (5), and (S)-N-(2-amino-3-phenylpropionyl)-3-(6-guanidohexanoylamido)pyrrolidine (6). Compounds were able to inhibit thrombin-induced human platelet activation even at low concentrations. In particular, among compounds in group A, compound 3 was found to be the most powerful thrombin receptor activation inhibitor, showing an IC50 of approximately 0.11 mM on platelet aggregation assay. Among compounds in group B, compound 4 was the most powerful to inhibit thrombin-induced platelet aggregation, showing an IC50 of approximately 0.09 mM. All compounds were also found to act as agonists in the rat aorta relaxation assay. Interestingly, the order or potency of these compounds as agonists of the endothelial thrombin receptor was the inverse of the order of potency of the same compounds as antagonists of the platelet thrombin receptor. Such compounds that are causing vasodilation while simultaneously inhibiting platelet aggregation would be very useful in preventing the installation of atherosclerotic lesions and deserve further investigation as potential drugs for treating cardiovascular diseases. The above findings coupled with computational analysis molecular dynamics experiments support also our hypothesis that a cluster of phenyl, guanidino, and amino groups is responsible for thrombin receptor triggering and activation.

  DOI：

  10.1021/jm031080v
• 作为产物：
  描述：

  2-乙酰基-5,5-二甲基-1,3-环己二酮 、 4-氨甲基哌啶 以 乙醇 为溶剂， 反应 3.0h， 以87.5%的产率得到4-[1-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethylamino]methylpiperidine
  参考文献：
  名称：

  三嗪树枝状聚合物与周围受正交保护的胺。用Dde和BOC基团掩盖胺提供了一种通过迭代合成携带受保护的醇和二硫化物的替代方法

  摘要：

  基于三聚氰胺的正交保护的树枝状聚合物，具有24个Boc保护的胺（Boc为叔丁氧羰基）和12个Dde保护的（Dde为N使用会聚途径在四个线性步骤中合成了-2-（4,4-二甲基-2,6-二氧代环己基）乙基）胺，总产率为43％，提供了5 g的产品。该树枝状大分子的合成后操作产生了一个57 kDa的大分子，带有聚（乙二醇）基团和吡啶二硫醚基团，分别通过氨基甲酸酯键和酰胺键连接。与已探究的其他基团（尤其是羟基）相比，这些正交保护的胺为化学修饰提供了更多的反应性手感。此外，事实证明，Dde基团比以前使用的二硫化物对所用的合成方法更稳定。一氯三嗪和二氯三嗪中间体可作为消除因三嗪环过度取代而产生的有害副产物的宝贵途径。

  DOI：

  10.1021/jo701320h

文献信息

• Identification of a Novel 4-Aminomethylpiperidine Class of M₃ Muscarinic Receptor Antagonists and Structural Insight into Their M₃ Selectivity
  作者：Yufu Sagara、Takeshi Sagara、Minaho Uchiyama、Sachie Otsuki、Toshifumi Kimura、Toru Fujikawa、Kazuhito Noguchi、Norikazu Ohtake

  DOI：10.1021/jm051205r

  日期：2006.9.1

  Identification of a novel class of potent and highly selective M-3 muscarinic antagonists is described. First, the structure-activity relationship in the cationic amine core of our previously reported triphenylpropionamide class of M-3 selective antagonists was explored by a small diamine library constructed in solid phase. This led to the identification of M-3 antagonists with a novel piperidine pharmacophore and significantly improved subtype selectivity from a previously reported class. Successive modification on the terminal triphenylpropionamide part of the newly identified class gave 14a as a potent M-3 selective antagonist that had > 100-fold selectivity versus the M-1, M-2, M-4, and M-5 receptors (M-3: K-i = 0.30 nM, M-1/M-3 = 570-fold, M-2/M-3 = 1600-fold, M-4/M-3 = 140-fold, M-5/M-3 = 12000-fold). The possible rationale for its extraordinarily higher subtype selectivity than reported M-3 antagonists was hypothesized by sequence alignment of multiple muscarinic receptors and a computational docking of 14a into transmembrane domains of M-3 receptors.
• Design and solid-phase synthesis of chiral acyclic and cyclic diamine ligands
  作者：Dehe Li、Dennis G. Hall

  DOI：10.1016/j.tetasy.2005.03.029

  日期：2005.5

  A model resin-bound oligoamide functionalized with a rationally designed non-interfering diamine spacer was reduced, with borane-THF to provide the corresponding diamine derivative. The latter was transformed using an efficient orthogonal sequence of transformations into two acyclic chiral model diamines 19 and 22 and two cyclic diamine ligands 23 and 24. (C) 2005 Elsevier Ltd. All rights reserved.
• Design and Synthesis of Novel Biologically Active Thrombin Receptor Non-Peptide Mimetics Based on the Pharmacophoric Cluster Phe/Arg/NH₂ of the Ser₄₂-Phe-Leu-Leu-Arg₄₆ Motif Sequence:  Platelet Aggregation and Relaxant Activities
  作者：Kostas Alexopoulos、Panagiotis Fatseas、Euthemia Melissari、Demetrios Vlahakos、Panagiota Roumelioti、Thomas Mavromoustakos、Stefan Mihailescu、Maria Christina Paredes-Carbajal、Dieter Mascher、John Matsoukas

  DOI：10.1021/jm031080v

  日期：2004.6.1

  The identification of the thrombin receptor has promoted the interest for the development of new therapeutic agents capable of selectively inhibiting unwanted biological effects of thrombin on various cell types. In this study we have designed and synthesized two series of new thrombin receptor antagonists based on the thrombin receptor motif sequence S42FLLR46, one possessing two (Phe/Arg) pharmacophoric groups and the other possessing three (Phe/Arg/NH2). N-(6-Guanidohexanoyl)-N'-(phenylacetyl)piperazine (1), N-(phenylacetyl)-4-(6-guanidohexanoylamidomethyl)piperidine (2), and N-(phenylacetyl)-3-(6-guanidohexanoylamido)pyrrolidine (3) (group A) carry the two pharmacophoric side chains of Phe and Arg residues incorporated on three different templates (piperazine, 4-aminomethylpiperidine, and 3-aminopyrrolidine). Compounds with three pharmacophoric groups (group B) were built similarly to group A using the same templates with the addition of an extra methylamino group leading to (S)-N-(6-guanidohexanoyl)-N'-(2-amino-3-phenylpropionyl)piperazine (4), (S)-N-(2-amino-3-phenylpropionyl)-4-(6-guanidohexanoylamidomethyl)piperidine (5), and (S)-N-(2-amino-3-phenylpropionyl)-3-(6-guanidohexanoylamido)pyrrolidine (6). Compounds were able to inhibit thrombin-induced human platelet activation even at low concentrations. In particular, among compounds in group A, compound 3 was found to be the most powerful thrombin receptor activation inhibitor, showing an IC50 of approximately 0.11 mM on platelet aggregation assay. Among compounds in group B, compound 4 was the most powerful to inhibit thrombin-induced platelet aggregation, showing an IC50 of approximately 0.09 mM. All compounds were also found to act as agonists in the rat aorta relaxation assay. Interestingly, the order or potency of these compounds as agonists of the endothelial thrombin receptor was the inverse of the order of potency of the same compounds as antagonists of the platelet thrombin receptor. Such compounds that are causing vasodilation while simultaneously inhibiting platelet aggregation would be very useful in preventing the installation of atherosclerotic lesions and deserve further investigation as potential drugs for treating cardiovascular diseases. The above findings coupled with computational analysis molecular dynamics experiments support also our hypothesis that a cluster of phenyl, guanidino, and amino groups is responsible for thrombin receptor triggering and activation.
• Triazine Dendrimers with Orthogonally Protected Amines on the Periphery. Masking Amines with Dde and BOC Groups Provides an Alternative to Carrying Protected Alcohols and Disulfides through an Iterative Synthesis
  作者：Alona P. Umali、Hannah L. Crampton、Eric E. Simanek

  DOI：10.1021/jo701320h

  日期：2007.12.1

  An orthogonally protected dendrimer based on melamine displaying 24 Boc-protected amines (Boc is t-butoxycarbonyl) and 12 Dde-protected (Dde is N-2-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl) amines was synthesized using a convergent route in four linear steps in 43% overall yield to provide 5 g of product. Postsynthetic manipulation of this dendrimer produced a 57 kDa macromolecule bearing poly(ethylene

  基于三聚氰胺的正交保护的树枝状聚合物，具有24个Boc保护的胺（Boc为叔丁氧羰基）和12个Dde保护的（Dde为N使用会聚途径在四个线性步骤中合成了-2-（4,4-二甲基-2,6-二氧代环己基）乙基）胺，总产率为43％，提供了5 g的产品。该树枝状大分子的合成后操作产生了一个57 kDa的大分子，带有聚（乙二醇）基团和吡啶二硫醚基团，分别通过氨基甲酸酯键和酰胺键连接。与已探究的其他基团（尤其是羟基）相比，这些正交保护的胺为化学修饰提供了更多的反应性手感。此外，事实证明，Dde基团比以前使用的二硫化物对所用的合成方法更稳定。一氯三嗪和二氯三嗪中间体可作为消除因三嗪环过度取代而产生的有害副产物的宝贵途径。