1-amino-2-(ethoxycarbonyl)pyridinium 2,4,6-trimethylbenzenesulfonate

• 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: 1-amino-2-(ethoxycarbonyl)pyridinium 2,4,6-trimethylbenzenesulfonate
• 英文别名: Ethyl 1-aminopyridin-1-ium-2-carboxylate;2,4,6-trimethylbenzenesulfonate
• 化学式: C₈H₁₁N₂O₂*C₉H₁₁O₃S
• 分子量: 366.438
• InChiKey: YWGMINYVDSMERU-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.38
• 重原子数：
  25
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  122
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  1-amino-2-(ethoxycarbonyl)pyridinium 2,4,6-trimethylbenzenesulfonate 在 劳森试剂 、 potassium carbonate 作用下， 以 甲苯 、 乙腈 为溶剂， 反应 92.0h， 生成 1-oxo-2-phenylpyrido<2,1-f><1,2,4>triazinium-3-thiolate
  参考文献：
  名称：

  2-烷氧基羰基环亚铵盐，在合成新的共轭甜菜碱中的有效1,4-偶极当量。

  摘要：

  通过使2-烷氧基羰基吡啶鎓N-基化物与异氰酸苯酯反应，制备了含有双环体系吡啶醇[1,2-a]吡嗪和吡啶基[2,1-f] [1,2,4]三嗪的几种杂环美索甜菜碱。和异硫氰酸酯。

  DOI：

  10.1016/s0040-4020(01)89900-2
• 作为产物：
  描述：

  2-吡啶甲酸乙酯 、 2,4,6-三甲基苯磺酰羟胺 以 二氯甲烷 为溶剂， 反应 2.25h， 以95%的产率得到1-amino-2-(ethoxycarbonyl)pyridinium 2,4,6-trimethylbenzenesulfonate
  参考文献：
  名称：

  Discovery of 2-{4-[(3S)-Piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (MK-4827): A Novel Oral Poly(ADP-ribose)polymerase (PARP) Inhibitor Efficacious in BRCA-1 and -2 Mutant Tumors

  摘要：

  We disclose the development of a novel series of 2-phenyl-2H-indazole-7-carboxamides as poly(ADPribose)polymerase (PARP) 1 and 2 inhibitors. This series was optimized to improve enzyme and cellular activity, and the resulting PARP inhibitors display antiproliferation activities against BRCA-1 and BRCA-2 deficient cancer cells, with high selectivity over BRCA proficient cells. Extrahepatic oxidation by CYP450 1A1 and 1A2 was identified as a metabolic concern, and strategies to improve pharmacokinetic properties are reported. These efforts culminated in the identification of 2-{4-[(3S)-piperidin-3yl]phenyl}-2H-indazole-7-carboxamide 56 (MK-4827), which displays good pharmacokinetic properties and is currently in phase I clinical trials. This compound displays excellent PARP 1 and 2 inhibition with IC50 = 3.8 and 2.1 nM, respectively, and in a whole cell assay, it inhibited PARP activity with EC50 = 4 nM and inhibited proliferation of cancer cells with mutant BRCA-1 and BRCA-2 with CC50 in the 10-100 nM range. Compound 56 was well tolerated in vivo and demonstrated efficacy as a single agent in a xenograft model of BRCA-1 deficient cancer.

  DOI：

  10.1021/jm901188v

文献信息

• New route to pyrido[1,2-b]pyridazinium inner salts. Evidence of a 1,3-dipolar cycloaddition-ring expansion process
  作者：Jesús Valenciano、Ana M. Cuadro、Juan J. Vaquero、Julio Alvarez-Builla

  DOI：10.1016/s0040-4039(98)02406-x

  日期：1999.1

  reacted with Michael acceptors, giving rise to the corresponding cycloadducts which, depending on their regioisomeric nature, subsequently undergo a ring expansion to give pyrido[1,2-b]pyridazinium inner salts.

  2-烷氧羰基吡啶鎓N-氨基化物与迈克尔受体反应时表现为1,3-偶极子，产生相应的环加合物，取决于其区域异构体性质，随后进行环扩环，使吡啶并[1,2- b ]吡啶鎓内部盐。
• 2-Alkoxycarbonylpyridinium N-Aminides:  1,3-Dipoles or 1,4-Nucleophile−Electrophile Synthons? Experimental and Theoretical Evidence for the Mechanism of Pyrido[1,2-<i>b</i>]pyridazinium Inner Salt Formation
  作者：Jesús Valenciano、Ana M. Cuadro、Juan J. Vaquero、Julio Alvarez-Builla、Raul Palmeiro、Obis Castaño

  DOI：10.1021/jo9909655

  日期：1999.12.1

  2-Alkoxycarbonylpyridinium N-aminides behave as 1,3-dipoles toward acetylenic compounds and as 1,4-nucleophile-electrophiles with heterocumulenes in a [4 + 2] cyclocondensation process, yielding in the latter case conjugated mesomeric betaines. These N-aminides also behave as 1,3-dipoles when reacted with olefinic dipolarophiles, producing the corresponding cycloadducts that, depending on their regioisomeric nature, subsequently undergo a ring expansion process to produce pyrido[1,2-b]-pyridazinium inner salts. A mechanistic investigation performed using both PM3 frontier molecular orbital (FMO) and potential energy surface (PES) analysis at the RHF/6-31+G* level indicates that both the cycloaddition reaction and the ring expansion occur in a concerted way rather than through a stepwise mechanism via a zwitterionic intermediate.
• Discovery of 2-{4-[(3<i>S</i>)-Piperidin-3-yl]phenyl}-2<i>H</i>-indazole-7-carboxamide (MK-4827): A Novel Oral Poly(ADP-ribose)polymerase (PARP) Inhibitor Efficacious in BRCA-1 and -2 Mutant Tumors
  作者：Philip Jones、Sergio Altamura、Julia Boueres、Federica Ferrigno、Massimiliano Fonsi、Claudia Giomini、Stefania Lamartina、Edith Monteagudo、Jesus M. Ontoria、Maria Vittoria Orsale、Maria Cecilia Palumbi、Silvia Pesci、Giuseppe Roscilli、Rita Scarpelli、Carsten Schultz-Fademrecht、Carlo Toniatti、Michael Rowley

  DOI：10.1021/jm901188v

  日期：2009.11.26

  We disclose the development of a novel series of 2-phenyl-2H-indazole-7-carboxamides as poly(ADPribose)polymerase (PARP) 1 and 2 inhibitors. This series was optimized to improve enzyme and cellular activity, and the resulting PARP inhibitors display antiproliferation activities against BRCA-1 and BRCA-2 deficient cancer cells, with high selectivity over BRCA proficient cells. Extrahepatic oxidation by CYP450 1A1 and 1A2 was identified as a metabolic concern, and strategies to improve pharmacokinetic properties are reported. These efforts culminated in the identification of 2-4-[(3S)-piperidin-3yl]phenyl}-2H-indazole-7-carboxamide 56 (MK-4827), which displays good pharmacokinetic properties and is currently in phase I clinical trials. This compound displays excellent PARP 1 and 2 inhibition with IC50 = 3.8 and 2.1 nM, respectively, and in a whole cell assay, it inhibited PARP activity with EC50 = 4 nM and inhibited proliferation of cancer cells with mutant BRCA-1 and BRCA-2 with CC50 in the 10-100 nM range. Compound 56 was well tolerated in vivo and demonstrated efficacy as a single agent in a xenograft model of BRCA-1 deficient cancer.
• 2-Alkoxycarbonylcycloimmonium ylides, efficient 1,4-dipole equivalents in the synthesis of new conjugated betaines.
  作者：Ana M. Cuadro、Jesús Valenciano、Juan J. Vaquero、José L. García Navío、Julio Alvarez-Builla

  DOI：10.1016/s0040-4020(01)89900-2

  日期：1993.4

  Several heterocyclic mesomeric betaines containing the bicyclic systems pyridol[1,2-a]pyrazine and pyrido [2,1-f][1,2,4]triazine have been prepared by reaction of 2-alkoxycarbonyl pyridinium N-ylides with phenyl isocyanate and isothiocyanate.

  通过使2-烷氧基羰基吡啶鎓N-基化物与异氰酸苯酯反应，制备了含有双环体系吡啶醇[1,2-a]吡嗪和吡啶基[2,1-f] [1,2,4]三嗪的几种杂环美索甜菜碱。和异硫氰酸酯。