(1R,3S)-1-(1,3-苯并二氧戊环-5-基)-2-(2-氯乙酰基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-3-羧酸甲酯 | 629652-44-4

• 物质功能分类: 分析化学 - 标准品 - 药典标准品和杂质标准品
• 分子结构分类: 有机化合物 - 生物碱及其衍生物 - 哈马拉生物碱
• 中文名称: (1R,3S)-1-(1,3-苯并二氧戊环-5-基)-2-(2-氯乙酰基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-3-羧酸甲酯
• 中文别名: 他达那非中间体异构体杂质
• 英文名称: (1R,3S)-1-benzo[1,3]dioxol-5-yl-2-(2-chloroacetyl)-2,3,4,9-tetrahydro-1H-β-carboline-3-carboxylic acid methyl ester
• 英文别名: methyl (1R,3S)-1-(benzo[d][1,3]dioxol-5-yl)-2-(2-chloroacetyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate；(1R,3S)-trans-methyl 1-(1,3-benzodioxol-5-yl)-2-(chloroacetyl)-2,3,4,9-tetrahydro-1H-β-carboline-3-carboxylate；methyl (1R,3S)-1-(3,4-methylenedioxyphenyl)-N-(2-chloroacetyl)-1,2,3,4-tetrahydro-β-carboline-3-carboxylate；(1R,3S)-1-(1,3-Benzodioxol-5-yl)-2-(2-chloroacetyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic Acid Methyl Ester；methyl (1R,3S)-1-(1,3-benzodioxol-5-yl)-2-(2-chloroacetyl)-1,3,4,9-tetrahydropyrido[3,4-b]indole-3-carboxylate
• CAS: 629652-44-4
• 化学式: C₂₂H₁₉ClN₂O₅
• 分子量: 426.856
• InChiKey: JUKHNCNDFOAFLT-HRAATJIYSA-N

物化性质

• 熔点：
  208 °C(Solv: ethyl ether (60-29-7))
• 沸点：
  627.5±55.0 °C(Predicted)
• 密度：
  1.445±0.06 g/cm3(Predicted)
• 溶解度：
  可溶于DMSO、甲醇（少量）

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  30
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  80.9
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (1R,3S)-1-(1,3-苯并二氧戊环-5-基)-2-(2-氯乙酰基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-3-羧酸甲酯 在 氨 作用下， 以 甲醇 为溶剂， 反应 20.0h， 以60%的产率得到N-去甲基ent-他达拉非
  参考文献：
  名称：

  PDE5 inhibitors: An original access to novel potent arylated analogues of tadalafil

  摘要：

  A method to access totally new analogues of tadalafil was explored, The Buchwald reaction was adapted and used to replace the methyl group of tadalafit by various aryl groups. Inhibition potencies on PDE5 of these analogues were determined and proved to be comparable to the one of tadalafil. Using the same route, compounds with the same level of activity but improved water solubility were produced by introducing a pyridine or a pyrimidine ring. This original route also opens access to new unpatented compounds. (c) 2006 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2006.10.069
• 作为产物：
  描述：

  L-色氨酸甲酯盐酸盐 在 三乙胺 作用下， 以 乙醇 、 二氯甲烷 为溶剂， 反应 30.0h， 生成 (1R,3S)-1-(1,3-苯并二氧戊环-5-基)-2-(2-氯乙酰基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-3-羧酸甲酯
  参考文献：
  名称：

  口服可利用的第一代乙酰胆碱酯酶（AChE）和磷酸二酯酶5（PDE5）的双目标选择性抑制剂的设计，合成和生物学评估

  摘要：

  通过重新利用和重新开发现有药物的药物发现策略，合理地设计，合成和评估了一系列新型他达拉非衍生物，以寻找双靶点AChE / PDE5抑制剂作为阿尔茨海默氏病（AD）的良好候选药物。在这些衍生物中，1p和1w表现出优异的选择性双靶AChE / PDE5抑制活性和改善的血脑屏障（BBB）渗透性。重要的是1w·Cit（柠檬酸盐为1w）可以逆转东pol碱诱导的AD小鼠的认知功能障碍，并在增强体内cAMP反应元件结合蛋白（CREB）磷酸化方面表现出优异的作用，这是记忆形成和突触可塑性的关键因素。此外，与hAChE和hPDE5A的1w分子对接模拟证实了我们的设计策略是合理的。总而言之，我们的研究提供了一种潜在的选择性双靶AChE / PDE5抑制剂，作为治疗AD的良好候选药物，它也可以被视为小分子探针，以验证体内新颖的AD治疗方法。

  DOI：

  10.1021/acschemneuro.7b00345

文献信息

• Chemical compounds
  申请人：——

  公开号：US20030225094A1

  公开（公告）日：2003-12-04

  Compounds of the general structural formula (I) and use of the compounds and salts and solvates thereof, as therapeutic agents. 1

  通用结构式（I）的化合物及其盐和溶剂合物的用途，作为治疗剂。
• Oncogenic-RAS-signal dependent lethal compounds
  申请人：Stockwell Brent R.

  公开号：US20100081654A1

  公开（公告）日：2010-04-01

  Compounds with cancer cell specific lethality are provided. In particular, RAS-selective lethal compounds and compositions are provided. Also provided are methods of screening for such compounds and methods of treating a condition in a mammal, by administering to the mammal a therapeutically effective amount of such compounds or compositions.

  提供了具有癌细胞特异性致死性的化合物。特别地，提供了选择性致死RAS化合物和组合物。还提供了筛选此类化合物的方法以及通过向哺乳动物投与此类化合物或组合物的治疗有效量来治疗哺乳动物病症的方法。
• The Discovery of Tadalafil:  A Novel and Highly Selective PDE5 Inhibitor. 2: 2,3,6,7,12,12a-hexahydropyrazino[1‘,2‘:1,6]pyrido[3,4-<i>b</i>]indole-1,4-dione Analogues
  作者：Alain Daugan、Pascal Grondin、Cécile Ruault、Anne-Charlotte Le Monnier de Gouville、Hervé Coste、Jean Michel Linget、Jorge Kirilovsky、François Hyafil、Richard Labaudinière

  DOI：10.1021/jm0300577

  日期：2003.10.1

  Modification of the hydantoin ring in the previously described lead compound 2a has led to the discovery of compound 12a, tadalafil, a highly potent and highly selective PDE5 inhibitor. The replacement of the hydantoin in compound 2a by a piperazinedione ring led to compound cis-11a which showed similar PDE5 inhibitory potency. Introduction of a 3,4-methylenedioxy substitution on the phenyl ring in position 6 led to a potent PDE5 inhibitor cis-11c with increased cellular potency. Optimization of the chain on the piperazinedione ring led to the identification of the racemic cis-N-methyl derivative 11i. High diastereospecificity for PDE5 inhibition was observed in the piperazinedione series with the cis-(6R,12aR) enantiomer displaying the highest PDE5 inhibitory activity. The piperazinedione 12a, tadalafil (GF196960), has been identified as a highly potent PDE5 inhibitor (IC50 = 5 nM) with high selectivity for PDE5 vs PDE1-4 and PDE6. Compound 12a displays 85-fold greater selectivity vs PDE6 than sildenafil 1.12a showed profound and long-lasting blood pressure lowering activity (30 mmHg/> 7 h) in the spontaneously hypertensive rat model after oral administration (5 mg/kg).
• US8546421B1
  申请人：——

  公开号：US8546421B1

  公开（公告）日：2013-10-01
• PDE5 inhibitors: An original access to novel potent arylated analogues of tadalafil
  作者：Terence Beghyn、Candide Hounsou、Benoit P. Deprez

  DOI：10.1016/j.bmcl.2006.10.069

  日期：2007.2

  A method to access totally new analogues of tadalafil was explored, The Buchwald reaction was adapted and used to replace the methyl group of tadalafit by various aryl groups. Inhibition potencies on PDE5 of these analogues were determined and proved to be comparable to the one of tadalafil. Using the same route, compounds with the same level of activity but improved water solubility were produced by introducing a pyridine or a pyrimidine ring. This original route also opens access to new unpatented compounds. (c) 2006 Elsevier Ltd. All rights reserved.