9-azabicyclo[3.3.1]nonan-3-yl-2-methoxy-5-methylphenylcarbamate

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 9-azabicyclo[3.3.1]nonan-3-yl-2-methoxy-5-methylphenylcarbamate
• 英文别名: 9-azabicyclo[3.3.1]nonan-3-yl N-(2-methoxy-5-methylphenyl)carbamate
• 化学式: C₁₇H₂₄N₂O₃
• 分子量: 304.389
• InChiKey: AJASUVMZHOIEPE-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  22
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.59
• 拓扑面积：
  59.6
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  1-溴-2-氟乙烷 、 9-azabicyclo[3.3.1]nonan-3-yl-2-methoxy-5-methylphenylcarbamate 在 potassium carbonate 作用下， 以 乙腈 为溶剂， 以51%的产率得到9-(2-fluoroethyl)-9-azabicyclo[3.3.1]nonan-3-yl-2-methoxy-5-methylphenylcarbamate
  参考文献：
  名称：

  New N-substituted 9-azabicyclo[3.3.1]nonan-3α-yl phenylcarbamate analogs as σ2 receptor ligands: Synthesis, in vitro characterization, and evaluation as PET imaging and chemosensitization agents

  摘要：

  A series of N-substituted 9-azabicyclo[3.3.1] nonan-3 alpha-yl phenylcarbamate analogs were synthesized. Among them, WC-26 and WC-59 were identified as the most potent sigma(2) receptor ligands (K-i = 2.58 and 0.82 nM, respectively) with high selectivity against sigma(1) (K-i of sigma(1)/sigma(2) ratio = 557 and 2087, respectively). [F-18] WC-59 was radiolabeled via a nucleophilic substitution of a mesylate precursor by [F-18]fluoride and in vitro direct binding studies of [F-18]WC-59 were conducted using membrane preparations from murine EMT-6 solid breast tumors. The results indicate that [F-18]WC-59 binds specifically to sigma(2) receptors in vitro (K-d = similar to 2 nM). Biodistribution studies of [F-18]WC-59 in EMT-6 tumor-bearing mice indicated that the tracer was a less suitable candidate for clinical imaging studies than existing F-18 labeled sigma(2) receptor ligands. The ability of WC-26 to enhance the cytotoxic effects of the chemotherapy drug, doxorubicin, was evaluated in cell culture using the mouse breast tumor EMT-6 and the human tumor MDA-MB435. WC-26 greatly increased the ability of doxorubicin to kill these two tumor cell lines in vitro. These results indicate that WC-26 is potentially a useful chemosensitizer for the treatment of cancer when combined with conventional chemotherapeutics. (c) 2009 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2008.12.025
• 作为产物：
  描述：

  9-benzyl-9-azabicyclo[3.3.1]nonan-3-yl-2-methoxy-5-methylphenylcarbamate 在 Pearlman's catalyst 、 甲酸铵 作用下， 以 乙酸乙酯 为溶剂， 反应 2.0h， 以100%的产率得到9-azabicyclo[3.3.1]nonan-3-yl-2-methoxy-5-methylphenylcarbamate
  参考文献：
  名称：

  New N-substituted 9-azabicyclo[3.3.1]nonan-3α-yl phenylcarbamate analogs as σ2 receptor ligands: Synthesis, in vitro characterization, and evaluation as PET imaging and chemosensitization agents

  摘要：

  A series of N-substituted 9-azabicyclo[3.3.1] nonan-3 alpha-yl phenylcarbamate analogs were synthesized. Among them, WC-26 and WC-59 were identified as the most potent sigma(2) receptor ligands (K-i = 2.58 and 0.82 nM, respectively) with high selectivity against sigma(1) (K-i of sigma(1)/sigma(2) ratio = 557 and 2087, respectively). [F-18] WC-59 was radiolabeled via a nucleophilic substitution of a mesylate precursor by [F-18]fluoride and in vitro direct binding studies of [F-18]WC-59 were conducted using membrane preparations from murine EMT-6 solid breast tumors. The results indicate that [F-18]WC-59 binds specifically to sigma(2) receptors in vitro (K-d = similar to 2 nM). Biodistribution studies of [F-18]WC-59 in EMT-6 tumor-bearing mice indicated that the tracer was a less suitable candidate for clinical imaging studies than existing F-18 labeled sigma(2) receptor ligands. The ability of WC-26 to enhance the cytotoxic effects of the chemotherapy drug, doxorubicin, was evaluated in cell culture using the mouse breast tumor EMT-6 and the human tumor MDA-MB435. WC-26 greatly increased the ability of doxorubicin to kill these two tumor cell lines in vitro. These results indicate that WC-26 is potentially a useful chemosensitizer for the treatment of cancer when combined with conventional chemotherapeutics. (c) 2009 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2008.12.025

文献信息

• Sigma 2 Receptor Ligands and Therapeutic Uses Therefor
  申请人：Mach Robert H.

  公开号：US20080161343A1

  公开（公告）日：2008-07-03

  A series of N-substituted 9-azabicyclo[3.3.1]nonan-3α-yl phenylcarbamate analogs are disclosed, as well as methods of their preparation. Their affinities for sigma (σ1 and σ2) receptors are described. Two new compounds, N-(9-(4-aminobutyl)-9-azabicyclo[3.3.1]nonan-3α-yl)-N′-(2-methoxy-5-methylphenyl)carbamate and N-(9-(6-aminohexyl)-9-azabicyclo[3.3.1]nonan-3α-yl)-N′-(2-methoxy-5-methylphenyl)carbamate, are shown to have a high affinity and selectivity for σ2 versus σ1 receptors. Among the disclosed compounds are biotinylated and fluorescent analogs. These compounds can serve as probes to the σ2 receptor. In addition, some disclosed compounds can induce apoptotic cell death by both caspase-dependent and caspase-independent mechanisms, and are effective for treatment of tumors. The compounds can be used as chemotherapeutics or chemosensitizers in the treatment of a wide variety of solid tumors.

  本文披露了一系列N-取代的9-氮杂双环[3.3.1]壬烷-3α-基苯基氨基甲酸酯类似物，以及它们的制备方法。描述了它们对sigma（σ1和σ2）受体的亲和力。展示了两种新化合物，即N-(9-(4-氨基丁基)-9-氮杂双环[3.3.1]壬烷-3α-基)-N′-(2-甲氧基-5-甲基苯基)氨基甲酸酯和N-(9-(6-氨基己基)-9-氮杂双环[3.3.1]壬烷-3α-基)-N′-(2-甲氧基-5-甲基苯基)氨基甲酸酯，它们被证明对σ2受体具有高亲和力和选择性，而非σ1受体。在披露的化合物中包括生物素化和荧光类似物。这些化合物可以作为对σ2受体的探针。此外，一些披露的化合物可以通过半胱氨酸依赖和半胱氨酸非依赖机制诱导凋亡细胞死亡，并且对肿瘤的治疗有效。这些化合物可以用作治疗各种固体肿瘤的化疗药物或化疗增敏剂。
• THERAPEUTIC USES OF BICYCLIC LIGANDS OF SIGMA 2 RECEPTOR
  申请人：Mach Robert H.

  公开号：US20100048614A1

  公开（公告）日：2010-02-25

  A series of N-substituted 9-azabicyclo[3.3.1]nonan-3α-yl phenylcarbamate analogs are disclosed, as well as methods of their preparation. Their affinities for sigma (σ1 and σ2) receptors are described. Two new compounds, N-(9-(4-aminobutyl)-9-azabicyclo[3.3.1]nonan-3α-yl)-N′-(2-methoxy-5-methylphenyl)carbamate and N-(9-(6-aminohexyl)-9-azabicyclo[3.3.1]nonan-3α-yl)-N′-(2-methoxy-5-methylphenyl)carbamate, are shown to have a high affinity and selectivity for σ2 versus σ1 receptors. Among the disclosed compounds are biotinylated and fluorescent analogs. These compounds can serve as probes to the σ2 receptor. In addition, some disclosed compounds can induce apoptotic cell death by both caspase-dependent and caspase-independent mechanisms, and are effective for treatment of tumors. The compounds can be used as chemotherapeutics or chemosensitizers in the treatment of a wide variety of solid tumors.
• SIGMA-2 RECEPTOR LIGAND DRUG CONJUGATES AS ANTITUMOR COMPOUNDS, METHODS OF SYNTHESIS AND USES THEREOF
  申请人：Washington University

  公开号：US20210221805A1

  公开（公告）日：2021-07-22

  Methods and compositions for treating cancers such as pancreatic cancer and synovial sarcoma are disclosed. Compounds comprising a sigma-2 receptor-binding moiety and a ferroptosis-inducing moiety are described. At least one described molecular species exhibits an IC 50 value below 5 μM against human pancreatic cancer cells in vitro. Administration of this species promoted shrinkage of pancreatic cancer tumors in a murine model system in vivo, and led to 100% survival of experimental animals over a time course in which control therapies provided only 30% or 40% survival. Methods of synthesis of molecular species are also disclosed.
• US7612085B2
  申请人：——

  公开号：US7612085B2

  公开（公告）日：2009-11-03
• US8168650B2
  申请人：——

  公开号：US8168650B2

  公开（公告）日：2012-05-01