6-(4-氯苯基)-2,2-二甲基-7-苯基-2,3-二氢-1H-吡咯里嗪 | 133111-56-5

• 物质功能分类: 医药中间体 - 原料药中间体
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯
• 中文名称: 6-(4-氯苯基)-2,2-二甲基-7-苯基-2,3-二氢-1H-吡咯里嗪
• 英文名称: 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizine
• 英文别名: 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-1,3-dihydropyrrolizine
• CAS: 133111-56-5
• 化学式: C₂₁H₂₀ClN
• 分子量: 321.85
• InChiKey: RPWLGSCXSKWSCD-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.7
• 重原子数：
  23
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  4.9
• 氢给体数：
  0
• 氢受体数：
  0

安全信息

• 海关编码：
  2933990090

反应信息

• 作为反应物：
  描述：

  6-(4-氯苯基)-2,2-二甲基-7-苯基-2,3-二氢-1H-吡咯里嗪 在 sodium hydroxide 、 铜 作用下， 以 乙醇 、 甲苯 为溶剂， 反应 0.42h， 生成 利克飞龙
  参考文献：
  名称：

  （6,7-二芳基二氢吡咯烷嗪-5-基）乙酸，一类新的有效的环加氧酶和5-脂氧合酶双重抑制剂。

  摘要：

  描述了一类新型的CO和5-LO的非抗氧化剂双重抑制剂。通过修饰吡咯烷嗪环的6-位上的苯基部分的取代模式，可以改变对CO和5-LO的活性之间的平衡。讨论了构效关系。具有4-Cl取代基（IC50 = 0.21 microM（CO）; 0.18 microM（5-LO））的化合物3e和具有4-OCH3取代基（IC50 = 0.1 microM（CO）; 0.24 microM（5-LO）的化合物3e）是这两种酶最有效且平衡最强的双重抑制剂。用牛血小板完整细胞测定法测定CO的抑制，用完整牛PMNL测定5-LO的抑制率。还在人细胞中研究了化合物3e。

  DOI：

  10.1021/jm00038a021
• 作为产物：
  描述：

  3,3-dimethyl-4-hydroxy butyronitrile 在 吡啶 、 氯化亚砜 、 碳酸氢钠 作用下， 以 乙醚 、 乙醇 为溶剂， 反应 41.0h， 生成 6-(4-氯苯基)-2,2-二甲基-7-苯基-2,3-二氢-1H-吡咯里嗪
  参考文献：
  名称：

  Investigations on cytotoxicity and anti-inflammatory potency of licofelone derivatives

  摘要：

  A series of C5-substituted licofelone ([2,2-dimethyl-6-(4-chlorophenyl)-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl]acetic acid) derivatives were developed by a parallel synthesis approach and investigated for cytotoxicity against MCF-7 and MDA-MB-231 cells as well as for anti-inflammatory potency in vitro and in vivo. Dependent on the C5-substituent, the compounds showed high selectivity for MCF-7 cells. Especially 2-oxoethyl benzoate derivatives were inactive at the MDA-MB-231 cell line and as active as 5-FU at MCF-7 cells. C5-acetyl (8a), -2-oxoethyl formiate (8e), -2-oxoethyl acetate (81) and -2-oxoethyl propionate (8g) derivatives showed growth inhibition at both cell lines, comparable with cisplatin. Modifications significantly reduced the inhibitory potency at COX-1 and COX-2 in vitro and in the xylene-induced ear swelling assay in mice. Only compound 8a was equipotent to licofelone, ibuprofen and celecoxibe in vivo. (C) 2011 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2011.01.002

文献信息

• Arylpyrrolizines as Inhibitors of Microsomal Prostaglandin E₂ Synthase-1 (mPGES-1) or as Dual Inhibitors of mPGES-1 and 5-Lipoxygenase (5-LOX)
  作者：Andy J. Liedtke、Peter R. W. E. F. Keck、Frank Lehmann、Andreas Koeberle、Oliver Werz、Stefan A. Laufer

  DOI：10.1021/jm900481c

  日期：2009.8.13

  We synthesized and evaluated inhibitors for the microsomal prostaglandin E2 synthase-1 (mPGES-1), based on the arylpyrrolizine scaffold. In a cell free mPGES-1 assay several “sulfonimides” exceeded our lead ML3000 (3) in potency. The most promising compound, the tolylsulfonimide 11f, revealed an IC50 of 2.1 μM and is equipotent to the literature reference molecule MK886 (1). Selected compounds also

  我们基于芳基吡咯烷嗪支架合成并评估了微粒体前列腺素E 2合酶1（mPGES-1）的抑制剂。在无细胞的mPGES-1分析中，几种“磺酰亚胺”的功效超过了我们的铅ML3000（3）。最有前途的化合物甲苯磺酰亚胺11f的IC 50为2.1μM，与文献参考分子MK886（1）等价。所选化合物还可以有效减少完整细胞中5-LOX产物的形成。孤立的COX的抑制作用有时会显着降低。
• Licofelone-Nitric Oxide Donors as Anticancer Agents
  作者：Wukun Liu、Jinpei Zhou、Yinglin Liu、Haoran Liu、Kerstin Bensdorf、Cancheng Guo、Ronald Gust

  DOI：10.1002/ardp.201000397

  日期：2011.8

  Five licofelone ([2,2‐dimethyl‐6‐(4‐chlorophenyl)‐7‐phenyl‐2,3‐dihydro‐1H‐pyrrolizin‐5‐yl]acetic acid) nitric oxide donor conjugates were developed by a parallel synthesis approach. The biological screening revealed that compounds with a propyl (6b), butyl (6c), or octyl (6d) chain between licofelone and the nitric oxide donor exhibited high antiproliferative potency at MCF‐7 and MDA‐MB–231 breast

  通过平行合成方法开发了五种licofelone（[2,2-二甲基-6-（4-氯苯基）-7-苯基-2,3-二氢-1H-吡咯嗪-5-基]乙酸）一氧化氮供体偶联物. 生物筛选显示，在 licofelone 和一氧化氮供体之间具有丙基 (6b)、丁基 (6c) 或辛基 (6d) 链的化合物在 MCF-7 和 MDA-MB-231 乳腺癌以及在 HT-29 结肠癌细胞。此外，6b-d 对 MDA-MB-231 细胞的细胞毒性至少比母体化合物 licofelone 高 2 倍，尽管它们对 COX-1 和 COX-2 的抑制活性较低。COX 抑制和生长抑制特性之间的相关性是不可见的。然而，这些化合物的高水平一氧化氮产生可能导致它们的高细胞毒活性。
• Synthetic studies towards ML-3000 a concise synthesis of this non-steroidal anti-inflammatory drug
  作者：Janine Cossy、Damien Belotti

  DOI：10.1016/s0040-4020(99)00176-3

  日期：1999.4

  ML-3000 was obtained from 1-chloro-3-phenyl-2-propyne in 8 steps with an overall yield of 19%. The key steps are a thermal acid-promoted bicyclization of an ω-acetylenic amino ester and a Suzuki cross-coupling reaction between a heteroaryl triflate and (4-chlorophenyl)boronic acid.

  从1-氯-3-苯基-2-丙炔分8步获得ML-3000，总产率为19％。关键步骤是ω-炔基氨基酯的热酸促进的双环化和三氟甲磺酸杂芳基酯与（4-氯苯基）硼酸之间的Suzuki交叉偶联反应。
• Synthesis and Biological Evaluation of Licofelone Derivatives as Anticancer and Anti-inflammatory Agents
  作者：Wukun Liu、Jinpei Zhou、Huibin Zhang、Hai Qian、Jiahan Yin、Kerstin Bensdorf、Ronald Gust

  DOI：10.2174/157018011797655223

  日期：2011.12.1

  Two C5-substituted licofelone derivatives were developed and investigated for cytotoxicity against mammary (MCF-7 and MDA-MB 231) as well as colon carcinoma (HT-29) cancer cells. Both compounds were at least 2-fold more active than 5-fluorouracil (5-FU) and licofelone against mammary carcinoma cells. At HT-29 cells, they were less active, but nevertheless distinctly as active as 5-FU and still 2-fold more active than licofelone. However, variation of the C5- carboxylic group results in an occasionally remarkable decrease of anti-inflammatory potency in in vitro and in vivo.

  研究人员开发了两种 C5 取代的利可非酮衍生物，并研究了它们对乳腺癌细胞（MCF-7 和 MDA-MB 231）以及结肠癌细胞（HT-29）的细胞毒性。这两种化合物对乳腺癌细胞的活性至少是 5-氟尿嘧啶（5-FU）和利可非酮的 2 倍。在 HT-29 细胞中，这两种化合物的活性较低，但与 5-FU 的活性相当，仍比利可非酮高出 2 倍。不过，C5-羧基的变化偶尔会导致体外和体内抗炎效力的显著下降。
• An efficient synthesis of 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizine, a key intermediate in the licofelone synthesis
  作者：Stanislav Rádl、Jan Stach、Josef Černý、Ondřej Klecán

  DOI：10.1135/cccc2009026

  日期：——

  An efficient synthesis of 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizine, a key intermediate for the synthesis of licofelone, an anti-inflammatory drug currently undergoing evaluation of the phase-III clinical studies, is described. The method is based on a novel synthesis of unstable 5-benzyl-3,3-dimethyl-3,4-dihydro-2H-pyrrole, which is then treated with 2-bromo-1-(4-chlorophenyl)ethan-1-one. 2,2-Dimethyl-5-phenylpent-4-ynal with benzylamines provides the corresponding Schiff bases. Migration of the C=N double bond in these N-(2,2-dimethyl-5-phenylpent-4-yn-1-ylidene)benzylamines into conjugation with the aromatic ring using various base/solvent systems was studied. Acid hydrolysis of the formed Schiff bases then provided 2,2-dimethyl-5-phenylpent-4-yn-1-amine and 2,2-dimethyl-5-phenylpenta-3,4-dien-1-amine; their ratio was influenced mainly by the reaction conditions. Cyclization of these amines using Ag or Au catalysts then led to 5-benzyl-3,3-dimethyl-3,4-dihydro-2H-pyrrole.

  描述了一种高效合成6-(4-氯苯基)-2,2-二甲基-7-苯基-2,3-二氢-1H-吡咯啉的方法，该化合物是合成抗炎药利可非来的关键中间体，目前正在接受III期临床研究评估。该方法基于一种新颖的合成不稳定的5-苄基-3,3-二甲基-3,4-二氢-2H-吡咯啉，然后用2-溴-1-(4-氯苯基)乙酮处理。2,2-二甲基-5-苯基戊-4-炔醛与苄胺反应形成相应的席夫碱。使用不同的碱/溶剂体系将这些N-(2,2-二甲基-5-苯基戊-4-炔-1-亚甲基)苄胺中的C=N双键迁移与芳环共轭进行了研究。然后对形成的席夫碱进行酸水解，得到2,2-二甲基-5-苯基戊-4-炔-1-胺和2,2-二甲基-5-苯基戊-3,4-二烯-1-胺；它们的比例主要受反应条件的影响。使用Ag或Au催化剂对这些胺进行环化，然后得到5-苄基-3,3-二甲基-3,4-二氢-2H-吡咯啉。