6-methylene-7a-phenyltetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one | 845256-51-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯烷类
• 英文名称: 6-methylene-7a-phenyltetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one
• 英文别名: 6-methylidene-7a-phenyl-5,7-dihydro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one
• CAS: 845256-51-1
• 化学式: C₁₃H₁₃NO₂
• 分子量: 215.252
• InChiKey: OYFPDUBUJNUJDC-UHFFFAOYSA-N

物化性质

• 沸点：
  397.2±42.0 °C(Predicted)
• 密度：
  1.24±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.6
• 重原子数：
  16
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.31
• 拓扑面积：
  29.5
• 氢给体数：
  0
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  6-methylene-7a-phenyltetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one 在 四(三苯基膦)钯 、 palladium 10% on activated carbon 咪唑 、 4-二甲氨基吡啶 、 sodium hydroxide 、 乙醇 、 1,4-环己二烯 、 水 、 sodium hexamethyldisilazane 、 sodium carbonate 、 臭氧 、 三乙胺 、 lithium chloride 作用下， 以 四氢呋喃 、 hexanes 、 乙二醇二甲醚 、 乙醇 、 二氯甲烷 、 醋酸异丙酯 、 水 、 二乙胺 、 N,N-二甲基甲酰胺 、 异丙醇 为溶剂， 反应 27.02h， 生成 (2S)-4-(2,5-difluorophenyl)-N-[(3R,4S)-3-fluoropiperidin-4-yl]-2-(hydroxymethyl)-N-methyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide
  参考文献：
  名称：

  WO2006/101780

  摘要：

  公开号：
• 作为产物：
  描述：

  N-benzylidenephenylglycine methyl ester 在 盐酸 、 sodium hydroxide 、 lithium aluminium tetrahydride 、 TEA 、 四丁基硫酸氢铵 、 sodium carbonate 作用下， 以 四氢呋喃 、 二氯甲烷 、 水 为溶剂， 生成 6-methylene-7a-phenyltetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one
  参考文献：
  名称：

  Kinesin spindle protein (KSP) inhibitors. Part V: Discovery of 2-propylamino-2,4-diaryl-2,5-dihydropyrroles as potent, water-soluble KSP inhibitors, and modulation of their basicity by β-fluorination to overcome cellular efflux by P-glycoprotein

  摘要：

  Installation of a C2-aminopropyl side chain to the 2,4-diaryl-2,5-dihydropyrrole series of kinesin spindle protein (KSP) inhibitors results in potent, water soluble compounds, but the aminopropyl group induces susceptibility to cellular efflux by P-glycoprotein (Pgp). We show that by carefully modulating the basicity of the amino group by beta-fluorination, this series of inhibitors maintains potency against KSP and has greatly improved efficacy in a Pgp-overexpressing cell line. The discovery that cellular efflux by Pgp can be overcome by carefully modulating the basicity of an amine may be of general use to medicinal chemists attempting to transform leading compounds into cancer cell- or CNS-penetrant drugs. (c) 2007 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2007.03.006

文献信息

• Mitotic kinesin inhibitors
  申请人：Coleman J. Paul

  公开号：US20050038074A1

  公开（公告）日：2005-02-17

  The present invention relates to dihydropyrrole compounds that are useful for treating cellular proliferative diseases, for treating disorders associated with KSP kinesin activity, and for inhibiting KSP kinesin. The invention is also related to compositions which comprise these compounds, and methods of using them to treat cancer in mammals.

  本发明涉及对治疗细胞增殖性疾病、治疗与KSP动力蛋白活性相关的疾病以及抑制KSP动力蛋白的二氢吡咯化合物。该发明还涉及包含这些化合物的组合物，以及利用它们治疗哺乳动物癌症的方法。
• Mitotic Kinesin Inhibitors
  申请人：Coleman Paul J.

  公开号：US20080207693A1

  公开（公告）日：2008-08-28

  The present invention relates to dihydropyrazole compounds that are useful for treating cellular proliferative diseases, for treating disorders associated with KSP kinesin activity, and for inhibiting KSP kinesin. The invention also related to compositions which comprise these compounds, and methods of using them to treat cancer in mammals.

  本发明涉及二氢吡唑化合物，对于治疗细胞增殖性疾病，治疗与KSP动力蛋白活性相关的疾病，以及抑制KSP动力蛋白具有用处。该发明还涉及包含这些化合物的组合物，以及使用它们治疗哺乳动物癌症的方法。
• Kinesin Spindle Protein (KSP) Inhibitors. 9. Discovery of (2<i>S</i>)-4-(2,5-Difluorophenyl)-<i>N</i>-[(3<i>R</i>,4<i>S</i>)-3-fluoro-1-methylpiperidin-4-yl]-2-(hydroxymethyl)-<i>N</i>-methyl-2-phenyl-2,5-dihydro-1<i>H</i>-pyrrole-1-carboxamide (MK-0731) for the Treatment of Taxane-Refractory Cancer
  作者：Christopher D. Cox、Paul J. Coleman、Michael J. Breslin、David B. Whitman、Robert M. Garbaccio、Mark E. Fraley、Carolyn A. Buser、Eileen S. Walsh、Kelly Hamilton、Michael D. Schaber、Robert B. Lobell、Weikang Tao、Joseph P. Davide、Ronald E. Diehl、Marc T. Abrams、Vicki J. South、Hans E. Huber、Maricel Torrent、Thomayant Prueksaritanont、Chunze Li、Donald E. Slaughter、Elizabeth Mahan、Carmen Fernandez-Metzler、Youwei Yan、Lawrence C. Kuo、Nancy E. Kohl、George D. Hartman

  DOI：10.1021/jm800386y

  日期：2008.7.1

  Inhibition of kinesin spindle protein (KSP) is a novel mechanism for treatment of cancer with the potential to overcome limitations associated with currently employed cytotoxic agents. Herein, we describe a C2-hydroxymethyl dihydropyrrole KSP inhibitor ( 11) that circumvents hERG channel binding and poor in vivo potency, issues that limited earlier compounds from our program. However, introduction of the C2-hydroxymethyl group caused 11 to be a substrate for cellular efflux by P-glycoprotein (Pgp). Utilizing knowledge garnered from previous KSP inhibitors, we found that beta-fluorination modulated the p K a of the piperidine nitrogen and reduced Pgp efflux, but the resulting compound ( 14) generated a toxic metabolite in vivo. Incorporation of fluorine in a strategic, metabolically benign position by synthesis of an N-methyl-3-fluoro-4-(aminomethyl)piperidine urea led to compound 30 that has an optimal in vitro and metabolic profile. Compound 30 (MK-0731) was recently studied in a phase I clinical trial in patients with taxane-refractory solid tumors.
• [EN] MITOTIC KINESIN INHIBITORS<br/>[FR] INHIBITEURS DE KINESINE MITOTIQUE
  申请人：MERCK & CO INC

  公开号：WO2005018547A3

  公开（公告）日：2005-09-15
• MITOTIC KINESIN INHIBITORS
  申请人：Merck & Co., Inc.

  公开号：EP1664026B1

  公开（公告）日：2009-01-21