4-piperidinylmethyl 3,4-dihydro-2H-[1,3]oxazino[3,2-a]indole-10-carboxylate | 1247008-54-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: 4-piperidinylmethyl 3,4-dihydro-2H-[1,3]oxazino[3,2-a]indole-10-carboxylate
• 英文别名: piperidin-4-ylmethyl 3,4-dihydro-2H-[1,3]oxazino[3,2-a]indole-10-carboxylate
• CAS: 1247008-54-3
• 化学式: C₁₈H₂₂N₂O₃
• 分子量: 314.384
• InChiKey: LEOGZKZWYVTQIK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  23
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  52.5
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  4-piperidinylmethyl 3,4-dihydro-2H-[1,3]oxazino[3,2-a]indole-10-carboxylate 在 potassium carbonate 作用下， 以 二氯甲烷 、 乙腈 为溶剂， 反应 25.0h， 生成 C₃₃H₃₄N₂O₅*CH₄O₃S
  参考文献：
  名称：

  Acidic biphenyl derivatives: Synthesis and biological activity of a new series of potent 5-HT4 receptor antagonists

  摘要：

  Serotonin (5-hydroxytryptamine, 5-HT) is an important signaling molecule in the central nervous system (CNS) and in non-neuronal tissues and organs. Serotonin mediates a positive chronotropic and inotropic response through 5-HT4 receptors in the atrium and ventricle of the heart. Recent investigations have revealed increased expression of the 5-HT4(b) isoform in cardiomyocytes of chronic arrhythmic and failing hearts, and that the use of 5-HT4 receptor antagonists may be beneficial for treating these conditions. The 5-HT4 receptor possesses a transmembrane (TM) binding site important for ligand affinity and recognition, as well as a capacity to accommodate bulky ligands. A new series of peripherally-acting 5-HT4 receptor antagonists were prepared by combining the acidic biphenyl group from the class of angiotensin II receptor blockers (ARBs) with the SB207266 (piboserod) scaffold. The new compounds were pharmacologically evaluated and carboxylic acid 21 was identified as a potent and promising 5-HT4 receptor antagonist with moderate affinity for the AT(1) receptor. The permeability of carboxylic acid 21 in a Caco-2 assay was low and the corresponding prodrug esters 23a-f were therefore prepared. The pharmacokinetics of methyl ester 20 and n-butyl ester 23c were evaluated in a rat model, revealing incomplete metabolism to carboxylic acid 21. However, methyl ester 20 is a potent 5-HT4 receptor antagonist with binding affinities in the low picomolar range. Methyl ester 20 has promising oral bioavailability and pharmacokinetics and may target 5-HT4 receptors in both CNS and peripheral organs. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2013.09.004
• 作为产物：
  描述：

  1-苄基-4-哌啶甲醇 在 正丁基锂 、 palladium on activated charcoal 、 氢气 作用下， 以 四氢呋喃 、 甲醇 、 溶剂黄146 为溶剂， 20.0 ℃ 、500.01 kPa 条件下， 反应 60.08h， 生成 4-piperidinylmethyl 3,4-dihydro-2H-[1,3]oxazino[3,2-a]indole-10-carboxylate
  参考文献：
  名称：

  Synthesis and pharmacological properties of a new hydrophilic and orally bioavailable 5-HT4 antagonist

  摘要：

  5-HT4 receptor antagonists have been suggested to have clinical potential in treatment of atrial fibrillation, diarrhea-prone irritable bowel syndrome and urinary incontinence. Recently, the use of 5-HT4 antagonists has been suggested to have a therapeutic benefit in heart failure. Affinity for the hERG potassium ion channel and increased risk for prolonged QT intervals and arrhythmias has been observed for several 5-HT4 ligands. Serotonin may also have beneficial effects in the central nervous system (CNS) through stimulation of the 5-HT4 receptor, and reduced distribution of 5-HT4 antagonists to the CNS may therefore be an advantage. Replacing the amide and N-butyl side chain of the 5-HT4 receptor antagonist SB207266 with an ester and a benzyl dimethyl acetic acid group led to compound 9; a hydrophilic 5-HT4 antagonist with excellent receptor binding and low affinity for the hERG potassium ion channel. To increase oral bioavailability of carboxylic acid 9, two different prodrug approaches were applied. The tertbutyl prodrug 11 did not improve bioavailability, and LC-MS analysis revealed unmetabolized prodrug in the systemic circulation. The medoxomil ester prodrug 10 showed complete conversion and sufficient bioavailability of 9 to advance into further preclinical testing for treatment of heart failure. (C) 2013 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2013.03.060

文献信息

• Discovery and pharmacological profile of new hydrophilic 5-HT 4 receptor antagonists
  作者：Bjarne Brudeli、Mirusha Navaratnarajah、Kjetil Wessel Andressen、Ornella Manfra、Lise Román Moltzau、Nils Olav Nilsen、Finn Olav Levy、Jo Klaveness

  DOI：10.1016/j.bmcl.2014.06.083

  日期：2014.9

  The synthesis and pharmacological data of some new and potent hydrophilic 5-HT4 receptor antagonists are described. Propanediol derivative 25 was identified as a potent antagonist with low affinity for the hERG potassium channel and promising pharmacokinetics.

  描述了一些新的和有效的亲水性5-HT 4受体拮抗剂的合成和药理学数据。丙二醇衍生物25被确定为对hERG钾通道的低亲和力和有希望的药代动力学的强效拮抗剂。
• 5-HT RECEPTOR MODULATING COMPOUNDS
  申请人：Klaveness Jo

  公开号：US20120094989A1

  公开（公告）日：2012-04-19

  The present invention relates to compounds having 5-hydroxytryptamine receptor modulating activity, in particular compounds having an acidic moiety held distant from the 5-HT pharmacophore by a rigid linker group, to compositions containing such compounds and methods of treatment using them. Such compounds have an increased affinity for the 5-HT receptor and a reduced hERG effect. Certain compounds of the invention further exhibit an angiotensin II receptor modulating activity. Claimed are compounds of formula (I): HT-L-A. HT is a 5-HT receptor modulating moiety containing a basic nitrogen atom; A is an acid moiety; L is a linker moiety.

  本发明涉及具有5-羟色胺受体调节活性的化合物，特别是具有酸性基团，由刚性连接基团将其与5-HT药效团分开的化合物，以及含有这些化合物的组合物和使用它们的治疗方法。这些化合物具有对5-HT受体的增强亲和力和减少hERG效应。本发明的某些化合物还表现出血管紧张素II受体调节活性。本发明要求的是式(I)的化合物：HT-L-A。其中，HT是包含碱性氮原子的5-HT受体调节基团；A是酸性基团；L是连接基团。
• [EN] 5-HT RECEPTOR MODULATING COMPOUNDS<br/>[FR] COMPOSÉS MODULATEURS DU RÉCEPTEUR 5-HT
  申请人：SERODUS AS

  公开号：WO2010112865A1

  公开（公告）日：2010-10-07

  The present invention relates to compounds having 5-hydroxytryptamine receptor modulating activity, in particular compounds having an acidic moiety held distant from the 5-HT pharmacophore by a rigid linker group, to compositions containing such compounds and methods of treatment using them. Such compounds have an increased affinity for the 5-HT receptor and a reduced hERG effect. Certain compounds of the invention further exhibit an angiotensin II receptor modulating activity. Claimed are compounds of formula (I): HT - L - A. HT is a 5-HT receptor modulating moiety containing a basic nitrogen atom; A is an acid moiety; L is a linker moiety. Examples of particular preterred HT groups are: (a) (b). Examples of particular preferred L groups comprise formula ( Vl ) and (VII) moieties: Examples of acid moieties are: -C(O)OR I. -OP(O)(OR2)2, -P(O)(OR2)2, -SO2OR2, -S03H, -0S03H, -P(O)(OH )2.