(+/-) trans-methyl 1-(1,3-benzodioxol-5-yl)-2-(chloroacetyl)-2,3,4,9-tetrahydro-1H-β-carboline-3-carboxylate | 629652-42-2

• 物质功能分类: 有机原料 - 羧酸类化合物及衍生物
• 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
• 英文名称: (+/-) trans-methyl 1-(1,3-benzodioxol-5-yl)-2-(chloroacetyl)-2,3,4,9-tetrahydro-1H-β-carboline-3-carboxylate
• 英文别名: methyl (1S,3R)-1-(1,3-benzodioxol-5-yl)-2-(2-chloroacetyl)-1,3,4,9-tetrahydropyrido[3,4-b]indole-3-carboxylate
• CAS: 629652-42-2
• 化学式: C₂₂H₁₉ClN₂O₅
• 分子量: 426.856
• InChiKey: JUKHNCNDFOAFLT-IERDGZPVSA-N

物化性质

• 熔点：
  208-210oC
• 溶解度：
  可溶于二甲基亚砜、甲醇

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：

  (+/-) trans-methyl 1-(1,3-benzodioxol-5-yl)-2-(chloroacetyl)-2,3,4,9-tetrahydro-1H-β-carboline-3-carboxylate 在 氨 作用下， 以 甲醇 为溶剂， 反应 20.0h， 以65%的产率得到(6S,12aR)-6-benzo[1,3]dioxol-5-yl-2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione
  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：

  甲基色氨酸 在 碳酸氢钠 、 三氟乙酸 作用下， 以 二氯甲烷 、 氯仿 为溶剂， 反应 24.0h， 生成 (+/-) trans-methyl 1-(1,3-benzodioxol-5-yl)-2-(chloroacetyl)-2,3,4,9-tetrahydro-1H-β-carboline-3-carboxylate
  参考文献：
  名称：

  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-b]indole-1,4-dione Analogues

  摘要：

  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).

  DOI：

  10.1021/jm0300577

文献信息

• Design, Synthesis, and Biological Evaluation of Orally Available First-Generation Dual-Target Selective Inhibitors of Acetylcholinesterase (AChE) and Phosphodiesterase 5 (PDE5) for the Treatment of Alzheimer’s Disease
  作者：Fei Mao、Huan Wang、Wei Ni、Xinyu Zheng、Manjiong Wang、Keting Bao、Dazheng Ling、Xiaokang Li、Yixiang Xu、Haiyan Zhang、Jian Li

  DOI：10.1021/acschemneuro.7b00345

  日期：2018.2.21

  drug discovery strategies of repurposing and redeveloping existing drugs, a series of novel tadalafil derivatives were rationally designed, synthesized, and evaluated to seek dual-target AChE/PDE5 inhibitors as good candidate drugs for Alzheimer’s disease (AD). Among these derivatives, 1p and 1w exhibited excellent selective dual-target AChE/PDE5 inhibitory activities and improved blood-brain barrier

  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。
• CHIRAL TETRA-HYDRO BETA-CARBOLINE DERIVATIVES AND APPLICATIONS THEREOF AS ANTIPARASITIC COMPOUNDS
  申请人：Université de Lille 2 Droit et Santé

  公开号：EP1914235A1

  公开（公告）日：2008-04-23

  The invention relates to the use of chiral tetra-hydro β-carboline derivatives of formula (I) for the preparation of pharmaceutical composition for the prevention and/or the treatment of parasitic diseases involving parasites having a phosphodiesterase activity: or a pharmaceutically acceptable salt thereof, in which: - R1 and R2, identical or different, represent a hydrogen atom or a fluorine atom; - k is an integer equal to 0 or 1; - R3 is selected from the group consisting of: ■ a phenyl ring optionally substituted ■ a 3'-N-pyridine ring optionally substituted - R4 is a group selected in the group consisting of the following groups: -NH-A-R5, -NHC(O)-R5 and the groups of formulas (II-a) to (II-c) below: The invention also relates to some new chiral tetra-hydro β-carboline derivatives.

  该发明涉及使用手性四氢β-咔啉衍生物的化学式(I)来制备用于预防和/或治疗涉及具有磷酸二酯酶活性的寄生虫引起的寄生虫疾病的药物组合物，或其药用盐，其中：- R1和R2，相同或不同，代表氢原子或氟原子；- k为0或1的整数；- R3从以下群组中选择：■ 可选择取代的苯环■ 可选择取代的3'-N-吡啶环- R4是从以下群组中选择的一个基团：-NH-A-R5，-NHC(O)-R5和下面的化学式(II-a)到(II-c)的基团：该发明还涉及一些新的手性四氢β-咔啉衍生物。
• Two Concise Syntheses of Cialis via the<i>N</i>-Acyliminium Pictet-Spengler Reaction
  作者：A. Ganesan、Jefferson D. Revell、Natarajan Srinivasan

  DOI：10.1055/s-2004-825625

  日期：——

  The imine derived from piperonal and d-tryptophan ­methyl ester underwent N-acyliminium Pictet-Spengler reaction with either Fmoc-sarcosyl chloride or chloroacetyl chloride. The products were readily converted to the drug Cialis.

  从胡椒醛和D-色氨酸甲酯衍生的亚胺与Fmoc-肌氨酸氯或氯乙酰氯发生N-酰亚胺Pictet-Spengler反应。产物很容易转化为药物西力士。
• 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。
• Synthesis and SAR of tetracyclic pyrroloquinolones as phosphodiesterase 5 inhibitors
  作者：Weiqin Jiang、Vernon C Alford、Yuhong Qiu、Sheela Bhattacharjee、T.Matthew John、Donna Haynes-Johnson、Patricia J Kraft、Scott G Lundeen、Zhihua Sui

  DOI：10.1016/j.bmc.2003.12.044

  日期：2004.3

  The synthesis of the fused tetracyclic pyrroloquinolones 9a-i in four steps is described. The PDE5 inhibitory activities of these compounds, their selectivities against PDE1, PDE2, PDE3, PDE4 and PDE6, the preclinical pharmacokinetic assessments and the in vivo efficacy in increasing intracavernosal pressure are presented and discussed. (C) 2004 Elsevier Ltd. All rights reserved.