6-[2-(2-羟基乙基氨基)乙基]茚并[3,2-c]异喹啉-5,11-二酮 | 148317-76-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 异喹啉及其衍生物
• 中文名称: 6-[2-(2-羟基乙基氨基)乙基]茚并[3,2-c]异喹啉-5,11-二酮
• 英文名称: 6-[2-(2-hydroxyethyl)-aminoethyl]-5,11-dioxo-5,6-dihydro-11H-indeno[1,2-c]isoquinoline
• 英文别名: 6-[2-(2-hydroxyethyl)aminoethyl]-5,11-dioxo-5,6-dihydro-11H-indeno[1,2-c]isoquinoline；oracin；Oracine；6-[2-(2-hydroxyethylamino)ethyl]indeno[1,2-c]isoquinoline-5,11-dione
• CAS: 148317-76-4
• 化学式: C₂₀H₁₈N₂O₃
• 分子量: 334.375
• InChiKey: LRHPCRBOMKRVOA-UHFFFAOYSA-N

物化性质

• 沸点：
  627.7±55.0 °C(Predicted)
• 密度：
  1.38±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.3
• 重原子数：
  25
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.2
• 拓扑面积：
  69.6
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  6-[2-(2-羟基乙基氨基)乙基]茚并[3,2-c]异喹啉-5,11-二酮 在 NADPH-regenerating system 作用下， 以 phosphate buffer 为溶剂， 生成 (R)-11-Hydroxy-6-[2-(2-hydroxy-ethylamino)-ethyl]-6H,11H-indeno[1,2-c]isoquinolin-5-one
  参考文献：
  名称：

  Aldo-keto reductases (AKR) from the AKR1C subfamily catalyze the carbonyl reduction of the novel anticancer drug oracin in man

  摘要：

  In many cases, cancer chemotherapy still obtains unsatisfactory response rates, rare complete remissions and responses of relatively short duration. Therefore, more effective drugs with new structures against cancer are continuously sought. Oracin, 6-[2(2-hydroxyethyl)-aminoethyl]-5,11-dioxo-5,6-dihydro-11H-indeno[1,2-c]isoquinoline, is a new anticancer drug which is presently in phase 11 clinical trials. Pharmacokinetic studies have revealed that oracin undergoes metabolic inactivation by carbonyl reduction. Since metabolic inactivation contributes to chemotherapy resistance, detailed knowledge about the participating enzymes is necessary. In the present study, we identified three members of the aldo-keto reductase (AKR) superfamily to mediate oracin carbonyl reduction in man. For AKR1C1, 1C2 and 1C4, purified from human liver cytosol, we could determine the kinetics and catalytic efficiencies. In addition, we investigated the stereospecificity of formation of reduced oracin (DHO). Whereas AKR1C2 and 1C4 are exclusively (100%) stereospecific for (+)-DHO formation, some 3% of (-)-DHO formation was found for AKR1C1. On the other hand, the activity of AKR1C1 in overall oracin reduction was one order of magnitude higher compared to AKR1C2 and 1C4. Detailed knowledge about all enzymes involved in oracin detoxification may help to improve an anticancer regimen by co-application of respective inhibitors. (c) 2007 Elsevier Ireland Ltd. All rights reserved.

  DOI：

  10.1016/j.tox.2007.05.021
• 作为产物：
  描述：

  C.I.酸性橙108 、 6-(2-chloroethyl)-5H-indeno[1,2-c]isoquinoline-5,11(6H)-dione 在 potassium carbonate 作用下， 以 N-甲基乙酰胺 、 乙醇 为溶剂， 生成 6-[2-(2-羟基乙基氨基)乙基]茚并[3,2-c]异喹啉-5,11-二酮
  参考文献：
  名称：

  6-[X-(2-hydroxyethyl)

  摘要：

  描述了一种新的6-[X-(2-羟乙基)氨基烷基]-5,11-二氧化-5,6-二氢-11H-吲哚[1,2-c]异喹啉衍生物，其通式表示为(I)，其中X代表位于吲哚异喹啉基本结构的6位氮原子上的氨基烷基中碳原子的数量为0到5，它们与无机和有机酸的盐以及它们的衍生物。最好通过以下过程制备抗肿瘤有效的吲哚异喹啉衍生物：将吲哚[1,2-c]异香豆素和/或1-甲氧基-2-(2-甲氧羰基苯基)-1-吲哚-3-酮与N-(羟乙基)烷基二胺在适当的无水溶剂介质中反应，最好是二甲基甲酰胺，在升高的温度下。另一种制备方法是在适当的溶剂中，最好是二甲基甲酰胺，在无水碳酸钾的存在下将6-(X-氯代烷基)-5,11-二氧化-5,6-二氢-11H-吲哚[1,2-c]异喹啉与2-氨基乙醇反应。新化合物，其衍生物和盐对于制备用于哺乳动物恶性肿瘤治疗的药物和组合物是有用的。

  公开号：

  US05597831A1

文献信息

• [EN] 6((2-HYDROXYETHYL)AMINO ALKYL)-5,11-DIOXO-5,6-DIHYDRO-11-H-INDENO(1,2-C)ISOQUINOLINE AND THEIR USE AS ANTINEOPLASTIC AGENTS
  申请人：VYZKUMNY USTAV PRO FARMACII A BIOCHEMII, S.P.

  公开号：WO1993005023A1

  公开（公告）日：1993-03-18

  (EN) New 6-[X-(2-hydroxyethyl)aminoalkyl]-5,11-dioxo-5,6-dihydro-11H-indeno[1,2-c]isochinoline derivatives represented by general formula (I), in which X stands for the number of carbon atoms from 0 to 5 in aminoalkyl group situated on nitrogen atom in position 6 of the indenoisochinoline fundamental structure, their salts with inorganic and organic acids and their derivatives were described. Antitumorously effective indenoisochinoline derivatives are most preferably prepared by the process in which the indeno[1,2-c]isocoumarine and/or 1-methoxy-2-(2-methoxycarbonylphenyl)-1-inden-3-one, respectively, comprises reacting with N-(hydroxyethyl)alkylen diamine in a medium of suitable aprotic solvent, preferably dimethylformamide, and at increased temperature. Another process for the preparation comprises reacting 6-(X-chloroalkyl)-5,11-dioxo-5,6-dihydro-11H-indeno[1,2-c]isochinolines with 2-aminoethanol in suitable solvent, preferably dimethylformamide, in the presence of anhydrous potassium carbonate. New compounds, their derivatives and salts are useful for the preparation of drugs and compositions for the treatment of malignant neoplasias in mammals.(FR) Nouveaux dérivés de 6-[X-(2-hydroxyéthyl)aminoalkyl]-5,11-dioxo-5,6-dihydro-11H-indéno[1,2-c]isoquinoléine répondant à la formule générale (I), dans laquelle X représente le nombre d'atomes de carbone compris entre 0 et 5 dans le groupe aminoalkyle situé sur l'atome d'azote dans la position 6 de la structure fondamentale d'indénoisoquinoléine, leurs sels d'addition d'acides inorganiques ou organiques, et leurs dérivés. De préférence, on prépare les dérivés d'indénoisoquinoléine à efficacité antitumorale par un processus selon lequel on met en réaction, d'une part, l'indéno[1,2-c]isocoumarine et/ou le 1-méthoxy-2-(2-méthoxycarbonylphényl)-1-inden-3-one, respectivement, et, d'autre part, la N-(hydroxyéthyl)alkylènediamine dans un milieu constitué d'un solvant exempt de protons approprié, de préférence le diméthylformamide, et à une température accrue. Un autre processus de préparation consiste à mettre les 6-(X-chloroalkyl)-5,11-dioxo-5,6-dihydro-11H-indéno[1,2-c]isoquinoléines en réaction avec le 2-aminoéthanol dans un solvant approprié, de préférence le diméthylformamide, en présence de carbonate de potassium anhydre. Les nouveaux composés, leurs dérivés et leurs sels sont utilisés dans la préparation de médicaments et de compositions destinés au traitement des néoplasies malignes chez les mammifères.

  新的6-[X-(2-羟乙基)氨基烷基]-5,11-二氧代-5,6-二氢-11H-吲哚[1,2-c]异喹啉衍生物，其通式表示为(I)，其中X代表氨基烷基上的碳原子数，位于吲哚异喹啉基本结构的氮原子的位置6，其范围为0到5。它们的无机和有机酸盐以及它们的衍生物也被描述。最好的抗肿瘤效果的吲哚异喹啉衍生物是通过以下过程制备的：将吲哚[1,2-c]异香豆素和/或1-甲氧基-2-(2-甲氧羰基苯基)-1-吲哚-3-酮与N-(羟乙基)烷基二胺在适当的无质子溶剂介质中反应，最好是二甲基甲酰胺，且在升高的温度下。另一种制备方法是将6-(X-氯代烷基)-5,11-二氧代-5,6-二氢-11H-吲哚[1,2-c]异喹啉与2-氨基乙醇在适当的溶剂中反应，最好是二甲基甲酰胺，在无水碳酸钾的存在下。新化合物、其衍生物和盐对于制备用于哺乳动物恶性肿瘤治疗的药物和组合物是有用的。
• 6-(2-HYDROXYETHYLAMINOALKYL)-5,11-DIOXO-5,6-DIHYDRO-11H- INDENO[1,2-C]ISOQUINOLINES AND THEIR USE AS ANTINEOPLASTIC AGENTS
  申请人：VUFB, a.s.

  公开号：EP0643699B1

  公开（公告）日：1996-10-23
• US5597831A
  申请人：——

  公开号：US5597831A

  公开（公告）日：1997-01-28
• 6-[X-(2-hydroxyethyl)
  申请人：VUFB a.s

  公开号：US05597831A1

  公开（公告）日：1997-01-28

  ##STR1## New 6-[X-(2-hydroxyethyl)aminoalkyl]-5,11-dioxo-5,6-dihydro-11H-indeno[-1,2-c] isochinoline derivatives represented by general formula (I), in which X stands for the number of carbon atoms from 0 to 5 in aminoalkyl group situated on nitrogen atom in position 6 of the indenoisochinoline fundamental structure, their salts with inorganic and organic acids and their derivatives were described. Antitumorously effective indenoisochinoline derivatives are most preferably prepared by the process in which the indeno[1,2-c]isocoumarine and/or 1-methoxy-2-(2-methoxycarbonylphenyl)-1-inden-3-one, respectively, comprises reacting with N-(hydroxyethyl)alkylen diamine in a medium of suitable aprotic solvent, preferably dimethylformamide, and at increased temperature. Another process for the preparation comprises reacting 6-(X-chloroalkyl)-5,11-dioxo-5,6-dihydro-11H-indeno[1,2-c]isochinolines with 2-aminoethanol in suitable solvent, preferably dimethylformamide, in the presence of anhydrous potassium carbonate. New compounds, their derivatives and salts are useful for the preparation of drugs and compositions for the treatment of malignant neoplasias in mammals.

  描述了一种新的6-[X-(2-羟乙基)氨基烷基]-5,11-二氧化-5,6-二氢-11H-吲哚[1,2-c]异喹啉衍生物，其通式表示为(I)，其中X代表位于吲哚异喹啉基本结构的6位氮原子上的氨基烷基中碳原子的数量为0到5，它们与无机和有机酸的盐以及它们的衍生物。最好通过以下过程制备抗肿瘤有效的吲哚异喹啉衍生物：将吲哚[1,2-c]异香豆素和/或1-甲氧基-2-(2-甲氧羰基苯基)-1-吲哚-3-酮与N-(羟乙基)烷基二胺在适当的无水溶剂介质中反应，最好是二甲基甲酰胺，在升高的温度下。另一种制备方法是在适当的溶剂中，最好是二甲基甲酰胺，在无水碳酸钾的存在下将6-(X-氯代烷基)-5,11-二氧化-5,6-二氢-11H-吲哚[1,2-c]异喹啉与2-氨基乙醇反应。新化合物，其衍生物和盐对于制备用于哺乳动物恶性肿瘤治疗的药物和组合物是有用的。
• Aldo-keto reductases (AKR) from the AKR1C subfamily catalyze the carbonyl reduction of the novel anticancer drug oracin in man
  作者：V WSOL、B SZOTAKOVA、H MARTIN、E MASER

  DOI：10.1016/j.tox.2007.05.021

  日期：2007.9.5

  In many cases, cancer chemotherapy still obtains unsatisfactory response rates, rare complete remissions and responses of relatively short duration. Therefore, more effective drugs with new structures against cancer are continuously sought. Oracin, 6-[2(2-hydroxyethyl)-aminoethyl]-5,11-dioxo-5,6-dihydro-11H-indeno[1,2-c]isoquinoline, is a new anticancer drug which is presently in phase 11 clinical trials. Pharmacokinetic studies have revealed that oracin undergoes metabolic inactivation by carbonyl reduction. Since metabolic inactivation contributes to chemotherapy resistance, detailed knowledge about the participating enzymes is necessary. In the present study, we identified three members of the aldo-keto reductase (AKR) superfamily to mediate oracin carbonyl reduction in man. For AKR1C1, 1C2 and 1C4, purified from human liver cytosol, we could determine the kinetics and catalytic efficiencies. In addition, we investigated the stereospecificity of formation of reduced oracin (DHO). Whereas AKR1C2 and 1C4 are exclusively (100%) stereospecific for (+)-DHO formation, some 3% of (-)-DHO formation was found for AKR1C1. On the other hand, the activity of AKR1C1 in overall oracin reduction was one order of magnitude higher compared to AKR1C2 and 1C4. Detailed knowledge about all enzymes involved in oracin detoxification may help to improve an anticancer regimen by co-application of respective inhibitors. (c) 2007 Elsevier Ireland Ltd. All rights reserved.