methyl 4-(4-tert-butoxycarbonylaminophenoxy)thieno[2,3-c]pyridine-2-carboxylate | 251996-50-6

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: methyl 4-(4-tert-butoxycarbonylaminophenoxy)thieno[2,3-c]pyridine-2-carboxylate
• 英文别名: Methyl 4-((4-tert-butyloxycarbonylamino)phenoxy)thieno[2,3-c]pyridine-2-carboxylate；Methyl 4-[4-[(2-methylpropan-2-yl)oxycarbonylamino]phenoxy]thieno[2,3-c]pyridine-2-carboxylate
• CAS: 251996-50-6
• 化学式: C₂₀H₂₀N₂O₅S
• 分子量: 400.455
• InChiKey: QWPLZLNUQLBMBV-UHFFFAOYSA-N

物化性质

• 沸点：
  510.7±50.0 °C(Predicted)
• 密度：
  1.318±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.2
• 重原子数：
  28
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  115
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  methyl 4-(4-tert-butoxycarbonylaminophenoxy)thieno[2,3-c]pyridine-2-carboxylate 在 氨 、 三氟乙酸 作用下， 以 甲醇 为溶剂， 反应 25.0h， 生成 4-(4-aminophenoxy)thieno[2,3-c]pyridine-2-carboxamide
  参考文献：
  名称：

  Synthesis and Mode of Action of ¹²⁵I- and ³H-Labeled Thieno[2,3-c]pyridine Antagonists of Cell Adhesion Molecule Expression

  摘要：

  A series of thieno[2,3-c]pyridine antagonists of cell adhesion molecule (CAM) expression, such as A-205804 (1) and A-249377 (2), selectively suppressed the induced expression of E-selectin and ICAM-1 over VCAM-1. In an effort to explore the biological mechanism of action of these inhibitors, we synthesized I-125- and H-3-labeled thieno[2,3-c]pyridines 5 and 6. An isolated diazonium tetrafluoroborate salt efficiently trapped (NaI)-I-125 on very small scale (7.5 mug of (NaI)-I-125), providing the corresponding I-125-labeled thieno[2,3-c]pyridine in modest yield. Preliminary mechanistic investigations using these radiolabeled compounds revealed that, upon incubation with human umbilical vein endothelial cells (HUVECs), these inhibitors of CAM expression translocated to the cell nucleus and were noncovalently associated with macromolecules of molecular weight greater than 650 kDa.

  DOI：

  10.1021/jo016171j
• 作为产物：
  描述：

  3,5-二氯吡啶-4-甲醛 在 caesium carbonate 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 3.0h， 生成 methyl 4-(4-tert-butoxycarbonylaminophenoxy)thieno[2,3-c]pyridine-2-carboxylate
  参考文献：
  名称：

  Synthesis and Mode of Action of ¹²⁵I- and ³H-Labeled Thieno[2,3-c]pyridine Antagonists of Cell Adhesion Molecule Expression

  摘要：

  A series of thieno[2,3-c]pyridine antagonists of cell adhesion molecule (CAM) expression, such as A-205804 (1) and A-249377 (2), selectively suppressed the induced expression of E-selectin and ICAM-1 over VCAM-1. In an effort to explore the biological mechanism of action of these inhibitors, we synthesized I-125- and H-3-labeled thieno[2,3-c]pyridines 5 and 6. An isolated diazonium tetrafluoroborate salt efficiently trapped (NaI)-I-125 on very small scale (7.5 mug of (NaI)-I-125), providing the corresponding I-125-labeled thieno[2,3-c]pyridine in modest yield. Preliminary mechanistic investigations using these radiolabeled compounds revealed that, upon incubation with human umbilical vein endothelial cells (HUVECs), these inhibitors of CAM expression translocated to the cell nucleus and were noncovalently associated with macromolecules of molecular weight greater than 650 kDa.

  DOI：

  10.1021/jo016171j

文献信息

• Cell adhesion-inhibiting antiinflammatory compounds
  申请人：Abbott Laboratories

  公开号：US06232320B1

  公开（公告）日：2001-05-15

  Compounds having Formula I are useful for treating inflammation. Also disclosed are pharmaceutical compositions comprising compounds of Formula I, and methods of inhibiting/treating inflammatory diseases in a mammal.

  具有I式化学式的化合物对于治疗炎症是有用的。还公开了包含I式化合物的药物组合物，以及在哺乳动物中抑制/治疗炎症性疾病的方法。
• Selective Inhibition of ICAM-1 and E-Selectin Expression in Human Endothelial Cells. 2. Aryl Modifications of 4-(Aryloxy)thieno[2,3-<i>c</i>]pyridines with Fine-Tuning at C-2 Carbamides
  作者：Gui-Dong Zhu、David L. Arendsen、Indrani W. Gunawardana、Steven A. Boyd、Andrew O. Stewart、Dennis G. Fry、Barbara L. Cool、Lemma Kifle、Verlyn Schaefer、Joseph Meuth、Kennan C. Marsh、Anita J. Kempf-Grote、Patrick Kilgannon、W. Michael Gallatin、Gregory F. Okasinski

  DOI：10.1021/jm0101702

  日期：2001.10.1

  The elevated expression of cell adhesion molecules (CAMs) on the lumenal surface of vascular endothelial cells is a critical early event in the complex inflammatory process. The adhesive interactions of these CAMs that include E-selectin, ICAM-1, and VCAM-1 with their counterreceptors on leukocytes, such as integrins of the alpha (L)beta (2) family, result in migration of the leukocytes to the site of inflammation and cause tissue injury. Pharmaceutical agents that could suppress the induced expression of one or more of these cell adhesion molecules would provide a novel mechanism to attenuate the inflammatory responses associated with chronic inflammatory diseases. A-205804 (1), a potent and selective inhibitor of the induced expression of E-selectin and ICAM-1 over VCAM-1, was further modified with emphasis at the C-4 and C-2 positions to identify a more potent drug candidate with a good pharmacokinetic profile and physical properties. Replacement of the C-4 sulfur linkage in I with an oxygen atom eliminated one of the two major metabolites for this lead molecule. The para-position of the 4-phenoxy group of the thieno[2,3-c]pyridine lead is found to be very critical for a higher in vitro potency and selectivity of E-selectin and ICAM-1 over VCAM-1 expression. This position is presumably close to the solvent-accessible region of the target protein-inhibitor complex. An attempt to install a water-solubilizing group at the para-position of the phenoxy group to increase the aqueous solubility of this lead series through various linkages failed to provide an ideal inhibitor. Only small substituents such as fluorine are tolerated at the meta- and ortho-positions of the 4-phenoxy to retain a good in vitro potency. Bromo, trifluoromethyl, pyrazol-1-yl, and imidazol-1-yl are among the better substituents at the para-position. With fine-tuning at the C-2 position we discovered a series of very potent (IC50 < 5 nM for ICAM-1) and selective (> 200-fold vs VCAM-1) inhibitors with a good pharmacokinetic profile. Demonstrated efficacy in a rat rheumatoid arthritis model and in a mice asthma model with selected compounds is also reported.
• Development of a Potent, Specific CDK8 Kinase Inhibitor Which Phenocopies CDK8/19 Knockout Cells
  作者：Michael F. T. Koehler、Philippe Bergeron、Elizabeth M. Blackwood、Krista Bowman、Kevin R. Clark、Ron Firestein、James R. Kiefer、Klaus Maskos、Mark L. McCleland、Linda Orren、Laurent Salphati、Steve Schmidt、Elisabeth V. Schneider、Jiansheng Wu、Maureen H. Beresini

  DOI：10.1021/acsmedchemlett.5b00278

  日期：2016.3.10

  Beginning with promiscuous COT inhibitors, which were found to inhibit CDK8, a series of 6-aza-benzothiophene containing compounds were developed into potent, selective CDK8 inhibitors. When cocrystallized with CDK8 and cyclin C, these compounds exhibit an unusual binding mode, making a single hydrogen bond to the hinge residue A100, a second to K252, and a key cation-pi interaction with R356. Structure-based drug design resulted in tool compounds 13 and 32, which are highly potent, kinase selective, permeable compounds with a free fraction >2% and no measurable efflux. Despite these attractive properties, these compounds exhibit weak antiproliferative activity in the HCT-116 colon cancer cell line. Further examination of the activity of 32 in this cell line revealed that the compound reduced phosphorylation of the known CDK8 substrate STAT1 in a manner identical to a CDK8 knockout clone, illustrating the complex effects of inhibition of CDK8 kinase activity in proliferation in these cells.
• CELL ADHESION-INHIBITING ANTINFLAMMATORY COMPOUNDS
  申请人：ABBOTT LABORATORIES

  公开号：EP1090009A2

  公开（公告）日：2001-04-11
• US6232320B1
  申请人：——

  公开号：US6232320B1

  公开（公告）日：2001-05-15