8-(4-chlorophenyl)-8-hydroxy-5-methyl-8H-<1,4>thiazino<3,4-c><1,2,4>oxadiazol-3-one | 145193-13-1

• 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: 8-(4-chlorophenyl)-8-hydroxy-5-methyl-8H-<1,4>thiazino<3,4-c><1,2,4>oxadiazol-3-one
• 英文别名: 8-(4-chlorophenyl)-8-hydroxy-5-methyl-8H-[1,4]thiazino[3,4-c][1,2,4]oxadiazol-3-one；8-(4-Chlorophenyl)-8-hydroxy-5-methyl-[1,2,4]oxadiazolo[3,4-c][1,4]thiazin-3-one
• CAS: 145193-13-1
• 化学式: C₁₂H₉ClN₂O₃S
• 分子量: 296.734
• InChiKey: PFZYNEDQOMUHNJ-UHFFFAOYSA-N

物化性质

• 沸点：
  436.8±55.0 °C(Predicted)
• 密度：
  1.60±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  19
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  87.4
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  8-(4-chlorophenyl)-8-hydroxy-5-methyl-8H-<1,4>thiazino<3,4-c><1,2,4>oxadiazol-3-one 在 对甲苯磺酸 、 三乙胺 作用下， 以 甲苯 为溶剂， 反应 5.0h， 生成 8-(4-chlorophenyl)-5-methyl-8-(2-piperidin-1-ylethoxy)-8H-[1,2,4]oxadiazolo[3,4-c][1,4]thiazin-3-one
  参考文献：
  名称：

  Playing with Opening and Closing of Heterocycles: Using the Cusmano-Ruccia Reaction to Develop a Novel Class of Oxadiazolothiazinones, Active as Calcium Channel Modulators and P-Glycoprotein Inhibitors

  摘要：

  由于硝基咪唑衍生物的环到环转变，我们获得了一个分子骨架，适当修饰后能够通过阻断L型钙通道来降低心肌收缩力。先前，我们利用这个骨架开发了一个定量构效关系（QSAR）模型，并使用其中效力最强的二唑硫嗪酮作为基于配体的虚拟筛选模板。在此，我们扩展了化学修饰的多样性，提供了11种新衍生物的合成和体外数据，并且利用最新的计算机技术开发了一个新的三维QSAR模型。我们观察到了二唑酮部分的关键作用：鉴于跨膜通道蛋白中存在带正电的钙离子，我们假设二唑硫嗪酮、钙离子和蛋白质之间形成了三元复合物。通过生成药效团并将其对接进蛋白质的同源模型中，我们支持了这一假设。我们还利用对接实验研究了与P-糖蛋白同源模型的相互作用，这一系列的分子能够抑制P-糖蛋白，并为这个骨架在生物相互作用中的相关性提供了更多证据。

  DOI：

  10.3390/molecules191016543
• 作为产物：
  描述：

  6-(4-chlorophenyl)-3-methyl-5-nitrosoimidazo<2,1-b><1,3>-thiazole 在 盐酸 作用下， 以 1,4-二氧六环 为溶剂， 生成 8-(4-chlorophenyl)-8-hydroxy-5-methyl-8H-<1,4>thiazino<3,4-c><1,2,4>oxadiazol-3-one
  参考文献：
  名称：

  A new ring transformation: conversion of 6-p-chlorophenyl-3-methyl-5-nitrosoimidazo[2,1-b]thiazole into 8-p-chlorophenyl-8-hydroxy-5-methyl-3-oxo-1,2,4-oxadiazolo[3,4-c][1,4-]thiazine by the action of mineral acids

  摘要：

  6-对氯苯基-3-甲基-5-亚硝基咪唑并[2;1-b]噻唑1在室温下用稀盐酸在二恶烷中处理得到8-对氯苯基-8-羟基-5-甲基-3- oxo-1,2,4-恶二唑并[3,4-c][1,4]噻嗪2，含有新的稠环体系，其分子结构通过物理方法（1H和13C NMR、电子碰撞质量和红外光谱，以及 XRD）。

  DOI：

  10.1039/c39920001394

文献信息

• Ring–ring interconversion: the rearrangement of 6-(4-chlorophenyl)-3-methyl-5-nitrosoimidazo[2,1-b][1,3]thiazole into 8-(4-chlorophenyl)-8-hydroxy-5-methyl-8H-[1,4]thiazino[3,4-c][1,2,4]oxadiazol-3-one. Elucidation of the reaction product through spectroscopic and X-ray crystal structure analysis
  作者：Aldo Andreani、Roberta Billi、Barbara Cosimelli、Angelo Mugnoli、Mirella Rambaldi、Domenico Spinelli

  DOI：10.1039/a701909b

  日期：——

  The reactivity of 6-(4-chlorophenyl)-3-methyl-5-nitrosoimidazo[2,1-b][1,3]thiazole (a member of a class of mutagenic compounds) with hydrochloric acid in ethanol has been investigated and the nature of the reaction product unambiguously established on the basis of infrared, NMR and mass spectra and a crystal structure determination.

  研究了6-（4-氯苯基）-3-甲基-5-亚硝基磺并咪唑[2,1- b ] [1,3]噻唑（一种致突变化合物的成员）与盐酸在乙醇中的反应性，并对其进行了研究。反应产物的性质基于红外，NMR和质谱以及晶体结构的确定而明确地确定。
• A New Class of Selective Myocardial Calcium Channel Modulators. 2. Role of the Acetal Chain in Oxadiazol-3-one Derivatives
  作者：Roberta Budriesi、Emanuele Carosati、Alberto Chiarini、Barbara Cosimelli、Gabriele Cruciani、Pierfranco Ioan、Domenico Spinelli、Raffaella Spisani

  DOI：10.1021/jm0493414

  日期：2005.4.1

  In the framework of the continuing interest of this research group in the use of 8-aryl-8-hydroxy-8H-[1,4]thiazino[3,4-c] [1,2,4]-oxadiazol-3-ones (1) as calcium entry blockers, a number of acetals were synthesized and assayed "in vitro". All of them are structurally related to diltiazem and pyrrolobenzothiazines. The effect on the biological profile was measured by functional assays for a wide variety of acetal residues: saturated linear and branched chains, short and long unsaturated E and/or Z chains as well as benzyl and methylcyclohexyl residues. From selective assays on the most active derivative (5b) (EC50 = 0.04 mu M), which is 20 times more active than diltiazern (EC50 = 0.79 mu M), a muscarinic or adenosinic mechanism of action was excluded. A 3D QSAR model was obtained and validated with homologous literature data, and a virtual receptor scheme was derived for the unknown binding site. The following pharmacophoric features favorably affect the potency: one positively charged center, three lipophilic groups, and two hydrogen-bonding acceptor groups.
• Inhibition of MDR1 Activity in Vitro by a Novel Class of Diltiazem Analogues: Toward New Candidates
  作者：Maurizio Viale、Cinzia Cordazzo、Barbara Cosimelli、Daniela de Totero、Patrizio Castagnola、Cinzia Aiello、Elda Severi、Giovanni Petrillo、Maurizio Cianfriglia、Domenico Spinelli

  DOI：10.1021/jm801195k

  日期：2009.1.22

  The reversal of multidrug resistance by 22 molecules [8-aryl-8-hydroxy-5-R'-8H-[1,4]thiazino[3,4-c]-[1,2,4]oxadiazol-3-ones (1a-i) and 8-aryl-8-alkoxy-5-methyl-8H-[1,4]thiazino[3,4-c][1,2,4]oxadiazol-3-ones (2a-m)] related to myocardial-calcium-channel-modulator diltiazem was studied in multidrug resistant A2780/DX3 and their sensitive counterpart A2780 cells. MTT, cytofluorimetry assays, and fluorescence microscopy analyses were used to define activity and accumulation of doxorubicin with or without the diltiazem-like modulators. Of the 22 molecules, 1a, 2f, 2g, and 2m were able to overcome the established criteria for the selection in A2780/DX3 cells (IC50 reduction >= 25%), but only 2f, 2g, and 2m caused a significant increase of intracellular accumulation of doxorubicin. In conclusion, experiments lead to the identification of three diltiazem-like molecules able to increase the intracellular accumulation of doxorubicin by inhibiting the MDR1 function, thus potentiating its anti proliferative activity in multidrug resistant A2780/DX3 cells.
• Ring-ring interconversions. Part 2. Effect of the substituent on the rearrangement of 6-aryl-3-methyl-5-nitrosoimidazo[2,1-b][1,3]thiazoles into 8-aryl-8-hydroxy-5-methyl-8H-[1,4]thiazino[3,4-c][1,2,4]oxadiazol-3-ones. A novel class of potential antitumor agents
  作者：Roberta Billi、Barbara Cosimelli、Domenico Spinelli、Mirella Rambaldi

  DOI：10.1016/s0040-4020(99)00189-1

  日期：1999.4

  The reaction of several 6-aryl-3-methyl-5-nitrosoimidazo[2,1-b][1,3]thiazoles with hydrochloric acid by refluxing in ethanol gives new 8-aryl-8-hydroxy-5-methyl-8H-[1,4]thiazino[3,4-c] [1,2,4]oxadiazol-3-ones for testing of their biological activity. By carrying out the reaction at room temperature it has been possible to isolate reaction intermediates to which structures have been assigned. This study has provided information on the reaction mechanism and on the effect of the substituent in the phenyl ring on the yield of the reaction. (C) 1999 Elsevier Science Ltd. All rights reserved.
• Cardiovascular Characterization of [1,4]Thiazino[3,4-<i>c</i>][1,2,4]oxadiazol-1-one Derivatives:  Selective Myocardial Calcium Channel Modulators
  作者：Roberta Budriesi、Barbara Cosimelli、Pierfranco Ioan、Camilla Zaira Lanza、Domenico Spinelli、Alberto Chiarini

  DOI：10.1021/jm020815d

  日期：2002.8.1

  As an extension of previous investigations (Tetrahedron 1999, 55, 5433-5440; J. Heterocycl. Chem. 2000, 37, 875-878), a series of 21 [1,4]thiazino[3,4-c][1,2,4]oxadiazolones, which has already been synthesized (except for compounds 5a, 5b, 6), was evaluated as calcium entry blockers by functional studies, namely, in isolated guinea-pig left and right atria and K+-depolarized aortic strips. With the aim of investigating the effect of a condensed benzene ring on the molecular structure and the influence of substituents on the 8-phenyl ring of 4a, ab initio computations (RHF/3-21*G) were performed on compounds 3, 4a-d, 4f, and 4k. The results obtained show that many of the compounds studied are potent and selective negative inotropic agents; in particular, compounds 4e and 4f are about 3- and 2-fold more potent than diltiazem, respectively.